TW200302728A - Substituted amines as IgE inhibitors - Google Patents

Substituted amines as IgE inhibitors Download PDF

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TW200302728A
TW200302728A TW092102250A TW92102250A TW200302728A TW 200302728 A TW200302728 A TW 200302728A TW 092102250 A TW092102250 A TW 092102250A TW 92102250 A TW92102250 A TW 92102250A TW 200302728 A TW200302728 A TW 200302728A
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alkyl
hydrogen
group
formula
compound
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TW092102250A
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Murty Bulusu
Peter Ettmayer
Klaus Weigand
Max Woisetschlager
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Novartis Ag
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Priority claimed from GB0221953A external-priority patent/GB0221953D0/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

An amine, which is substituted by phenyl-substituted pyrimidin; and phenyl; and a third substituent and its use as a pharmaceutical.

Description

200302728 ⑴ 玖、發明說明 (發明說明應敘明：發明所屬之技術領域、先前技術、内容、實施方式及圖式簡單説明) 技術領域 • F I ·， 本發明係關於有機化合物，如具有藥物如IgE合成抑制 之活性之經取代胺。 ^ 發明内容 於一方面，本發明—提供下_式_之_-化__合_物一 ’ 一 -----200302728 玖 玖, description of the invention (the description of the invention should state: the technical field to which the invention belongs, the prior art, the content, the embodiments, and a brief description of the drawings) Technical Field • FI ·, This invention is about organic compounds, such as drugs with IgE Synthesis of a substituted amine with inhibited activity. ^ SUMMARY OF THE INVENTION In one aspect, the present invention provides the following _form_ 之 _- 化 __ 合 _ 物 一 ’one -----

其中 R!為鹵素或鹵化（C^.4)烷基， R2為氫、鹵素或鹵化（Ci.4)烷基， R3為鹵素或鹵化（Ci-4)烷基， β R4為氫、（Cu)烷基、娌（Ci_6)烷基或下列式之族群 -CO-R5、 -CO-(CH2)m-OR6、 -CO-CO_R7、 -CO-CO-OR8、 CO-N(R9Ri0)、 v .C〇.(CH2)n-CO-R11 ^ -CO-(CHRi5)-〇-(CH2)〇-CO-Rii > -C0_(CH2)p-0-(CH2)q-0_(CH2)r-R16、 -C0-0-(CH2)s-0-C0-R17、 200302728 (2) -C0-0-(CH2)t-N(R18R19)、 -CO-O-(CH2)u-NH-CO-CH(NH2)-R20、或 -C0-0-(CH2)w-NH-C0-R17，其中 R5為氫、（Cu)烷基、（C3_8)環烷基、胺基、（Ci.4) 烷胺基、二（CL4)烷胺基、芳基或為具有1至4個選 自N、Ο或S之雜原子的5或6員雜環系統之雜環基， 為氫、（Cm)烷基、（C3_8)環烷基、芳基、經具有 1至4個選自N、Ο或S之雜原子的5或6員雜環系統 之雜環基取代的（Cy)烷基、胺基（C^)烷基、 (Cm)烷基胺（Cm)烷基、二（Cm)烷基胺（Cm)烷 基、羥（<^_6)烷基、羥（Cm)烷基胺（Cn)烷基或胺 基酸殘基，如-ch2-ch(nh2)-cooh， 117及R8各自獨立為（Ci-4)烷基、（c3_8)環烷基、芳基 或為具有1至4個選自Ν、Ο或S之雜原子的5或6員 雜環系統之雜環基， 119及R10各自獨立為氫或（Ci-4)烷基或R9及R10其中 之一為氫而另一為（C 3 ·8)環烷基、（C〗-4)烷基、芳 基或雜環基，Where R! Is halogen or halogenated (C ^ .4) alkyl, R2 is hydrogen, halogen or halogenated (Ci.4) alkyl, R3 is halogen or halogenated (Ci-4) alkyl, β R4 is hydrogen, ( Cu) alkyl, fluorene (Ci_6) alkyl or groups of the formula -CO-R5, -CO- (CH2) m-OR6, -CO-CO_R7, -CO-CO-OR8, CO-N (R9Ri0), v .C〇. (CH2) n-CO-R11 ^ -CO- (CHRi5) -〇- (CH2) 〇-CO-Rii > -C0_ (CH2) p-0- (CH2) q-0_ (CH2 ) r-R16, -C0-0- (CH2) s-0-C0-R17, 200302728 (2) -C0-0- (CH2) tN (R18R19), -CO-O- (CH2) u-NH- CO-CH (NH2) -R20, or -C0-0- (CH2) w-NH-C0-R17, where R5 is hydrogen, (Cu) alkyl, (C3_8) cycloalkyl, amine, (Ci. 4) Alkylamino, di (CL4) alkylamino, aryl or heterocyclic group of 5 or 6 membered heterocyclic system having 1 to 4 heteroatoms selected from N, 0 or S, is hydrogen, ( Cm) alkyl, (C3-8) cycloalkyl, aryl, (Cy) alkyl substituted with heterocyclyl of a 5 or 6-membered heterocyclic system having 1 to 4 heteroatoms selected from N, 0 or S , Amine (C ^) alkyl, (Cm) alkylamine (Cm) alkyl, di (Cm) alkylamine (Cm) alkyl, hydroxy (< 6) alkyl, hydroxy (Cm) alkane Alkyl (Cn) alkyl or amino acid residues Groups such as -ch2-ch (nh2) -cooh, 117 and R8 are each independently (Ci-4) alkyl, (c3_8) cycloalkyl, aryl or have 1 to 4 selected from N, O or S A heterocyclic group of a heteroatom 5 or 6 member heterocyclic system, 119 and R10 are each independently hydrogen or (Ci-4) alkyl or one of R9 and R10 is hydrogen and the other is (C 3 · 8) Cycloalkyl, (C〗 -4) alkyl, aryl or heterocyclic group,

Rn 為（Cm)烷基、_OR12、NR13R14、胺基酸、其（Cm) 烷基酯或其二（Ci.4)烷基酯， R12為氫或（Cm)烷基，Rn is (Cm) alkyl, —OR12, NR13R14, amino acid, its (Cm) alkyl ester or its di (Ci.4) alkyl ester, R12 is hydrogen or (Cm) alkyl,

Ri3及Rl4各自獨立為氫、（Ci-4)烷基、胺（Ci-6)烷 基、（Cm)烷基胺（Ci.6)烷基、二（Cm)烷基胺（Cm) 200302728 (3) R15為氫或（Cy)烷基，Ri3 and Rl4 are each independently hydrogen, (Ci-4) alkyl, amine (Ci-6) alkyl, (Cm) alkylamine (Ci.6) alkyl, di (Cm) alkylamine (Cm) 200302728 (3) R15 is hydrogen or (Cy) alkyl,

Rl6為氫、（Ci-4)燒基、獲基或複酸酉旨， 1^17為胺（。1_4)燒基、（€1_4)燒基胺（^!1.4)燒基或二 d-4)烷基胺（(^_4)烷基，R16 is hydrogen, (Ci-4) alkyl, phenyl or dicarboxylic acid, 1 ^ 17 is amine (.1-4) alkyl, (€ 1-4) amine (^ 1.4) or d- 4) alkylamine ((^ _4) alkyl,

Rl8為氫或（Ci_4)燒基5 R 1 9 為每（C 1 - 4 ) 基’ R20為d.4)烷基或羥（C^.4)烷基， m為0至4， η為2至8， 〇為0至4， ρ為0至4， q為1至8， r為0至4， s為1至4， t為1至4， u為1至6及 w為1至6 於另一方面，本發明提供式I之化合物，其中 -Ri為氯或三象甲基’ -R2為氫或三氟甲基’ -R3為氯、氟或三氟甲基， -R4為氫、（Ci-4)烷基（如甲基）、羥（Ci_4)烷基（如羥甲基） 、或下列式之族群 -CO-R5、 200302728 (4) -CO-(CH2)m-OR6、 _CO-CO-R7、 -CO-CO-OR8、 _CO-N(R9Ri〇)、 .CO-(CH2)n-CO-Rn ^R18 is hydrogen or (Ci_4) alkyl 5 R 1 9 is per (C 1-4) group 'R20 is d.4) alkyl or hydroxy (C ^ .4) alkyl, m is 0 to 4, and η is 2 to 8, 0 is 0 to 4, ρ is 0 to 4, q is 1 to 8, r is 0 to 4, s is 1 to 4, t is 1 to 4, u is 1 to 6, and w is 1 to 6 In another aspect, the present invention provides a compound of formula I, wherein -Ri is chloro or tris (methyl) '-R2 is hydrogen or trifluoromethyl' -R3 is chloro, fluoro or trifluoromethyl, and -R4 is Hydrogen, (Ci-4) alkyl (such as methyl), hydroxy (Ci_4) alkyl (such as hydroxymethyl), or a group of the formula -CO-R5, 200302728 (4) -CO- (CH2) m- OR6, _CO-CO-R7, -CO-CO-OR8, _CO-N (R9Ri〇), .CO- (CH2) n-CO-Rn ^

-CO-(CHR15)-〇-(CH2)0-CO-R1i ' -C0-(CH2)p-0-(CH2)q_0-(CH2)r-R16、 -C0-0-(CH2)s-0-C0-R17、 C0-0-(CH2)t-N(R18R19)、 -CO-O-(CH2)u-NH-CO_CH(NH2)-R20、或 -co-o-(ch2)w-nh-co-r17，其中 R5為氫、（Ci-4)烷基、（C3-8)環烷基、二甲胺基、芳 基或為具有1個ο作為雜原子之6員雜環系統之雜 環基（如 tetrahydropyranyl)，-CO- (CHR15) -〇- (CH2) 0-CO-R1i '-C0- (CH2) p-0- (CH2) q_0- (CH2) r-R16, -C0-0- (CH2) s- 0-C0-R17, C0-0- (CH2) tN (R18R19), -CO-O- (CH2) u-NH-CO_CH (NH2) -R20, or -co-o- (ch2) w-nh- co-r17, where R5 is hydrogen, (Ci-4) alkyl, (C3-8) cycloalkyl, dimethylamino, aryl, or a heterocyclic 6-membered heterocyclic system having one ο as a heteroatom Cyclic group (such as tetrahydropyranyl),

R6為氫、（Ci-4)烷基、經具有1或2個選自N或Ο之雜 原子的5或6員雜環系統之雜環基取代的（Ci.2)烷 基（如包括未經取代之峨洛淀、1，4 -氧氮陸圜及旅 畊、及受如（ChO烷基或（ChO羥烷基取代之哌畊） 、胺基（Cm)烷基、（Cm)烷基胺（Cm)烷基、二 (Cm)烷基胺（Cm)烷基、羥（Ch)烷基、羥（Cm) 烷基胺（Cy)烷基或胺基酸殘基，如 -CH2-CH(NH2)-COOH， 117及R8各自獨立為（CL2)烷基或苯基， 119及R1G各自獨立為氫或（Cm)烷基， 200302728 (5) Rll 為（Ci-2)fe 基、-0Rl2、NR13R14、胺基酸、其（Ci-2) 燒基S旨或其二（C i _ 2 )燒基g旨，較佳為由丙胺酸、苯 基丙胺酸、穀胺酸及賴胺酸組成之族群選出之胺 基酸，其中結合係經由6¾ -胺基或於如賴胺酸的情 況中經由ε -胺基達成， R12為氫或（Ci-2)烷基， Rl3及Rl4各自獨立為氮、（Ci_2)fe基、胺（Ci_4)fe 基、（Cu)烷基胺（Ci-4)烷基、二（Cu)烷基胺（Ci.4) 烷基， R15為氫或（Ci-2)烷基， 1 6為氫、（Ci-2)烷基、羧基或羧酸酯， Rl7為胺（Ci-2)烷基， Rl8為氫或（Ci_2)纪基’ R19為羥（Ci-2)烷基， R20為（Ci_2)燒基或經（Ci_2)挺基’ m為0或1， η為2至4， 〇為0或1， ρ為0至2， q為2至5， r為0至2， s為2， t為2， u為1至3及 -10- 200302728R6 is hydrogen, (Ci-4) alkyl, (Ci.2) alkyl substituted with a heterocyclyl of a 5 or 6-membered heterocyclic system having 1 or 2 heteroatoms selected from N or 0 (including Unsubstituted erogen, 1,4-oxazepine and brigade, and affected by (ChO alkyl or (ChO hydroxyalkyl substituted pipen), amine (Cm) alkyl, (Cm) Alkylamine (Cm) alkyl, di (Cm) alkylamine (Cm) alkyl, hydroxy (Ch) alkyl, hydroxy (Cm) alkylamine (Cy) alkyl or amino acid residues, such as- CH2-CH (NH2) -COOH, 117 and R8 are each independently (CL2) alkyl or phenyl, 119 and R1G are each independently hydrogen or (Cm) alkyl, 200302728 (5) Rll is (Ci-2) fe Group, -0Rl2, NR13R14, amino acid, its (Ci-2) alkyl group or its di (C i _ 2) alkyl group, preferably from alanine, phenylalanine, glutamic acid Amino acid selected from the group consisting of lysine and lysine, wherein the binding is achieved through 6¾-amino group or in the case of lysine, through ε-amino group, R12 is hydrogen or (Ci-2) alkyl, Rl3 And R14 are each independently nitrogen, (Ci_2) fe group, amine (Ci_4) fe group, (Cu) alkylamine (Ci-4) alkyl, and di (Cu) alkylamine (C i.4) alkyl, R15 is hydrogen or (Ci-2) alkyl, 16 is hydrogen, (Ci-2) alkyl, carboxyl, or carboxylic acid ester, R17 is amine (Ci-2) alkyl, Rl8 Is hydrogen or (Ci_2) alkyl group; R19 is hydroxy (Ci-2) alkyl, R20 is (Ci_2) alkyl or via (Ci_2) trityl group; m is 0 or 1, η is 2 to 4, and 〇 is 0 Or 1, ρ is 0 to 2, q is 2 to 5, r is 0 to 2, s is 2, t is 2, u is 1 to 3, and -10- 200302728

⑹ w為1至3 於另一方面，本發明提供式I之化合物，由N-[4-(3-氯-苯基密淀基]-N-(4-氯-3 -三氟i甲基-苯基）-胺、 N_[4-(3 -三氟1甲基-苯基）-口密淀-2-基]-N-(4 -氣-3-三氣甲基 -苯基）-胺、N-[4-(3 -二氟j甲基-苯基）密淀-2-基]-N-(4 -氯 -3-三氟甲基·苯基）-胺、N-[4_(3-三氟甲基-苯基）·嘧啶- 2-基]-N-(4-三氟甲基-苯基）-胺、及N-[4-(3-氯-苯基）-嘧啶 -2-基]三氟甲基-苯基）-胺組成之族群選出，其中胺 基進一步受R4取代，其中R4為如上定義。 於再另一方面，本發明提供式I之化合物，其中 -R1為氯’ -R2為氫’ -R3為二氣甲基及 -R4為氫。 於再另一方面，本發明提供式I之化合物，其中⑹w is 1 to 3 In another aspect, the present invention provides a compound of formula I, consisting of N- [4- (3-chloro-phenyl denselyl] -N- (4-chloro-3 -trifluoroimide) -Phenyl) -amine, N_ [4- (3-trifluoro1methyl-phenyl) -Komimitsu-2-yl] -N- (4-Ga-3-trifluoromethyl-phenyl ) -Amine, N- [4- (3-difluorojmethyl-phenyl) dense lake-2-yl] -N- (4-chloro-3-trifluoromethyl · phenyl) -amine, N -[4_ (3-trifluoromethyl-phenyl) · pyrimidin-2-yl] -N- (4-trifluoromethyl-phenyl) -amine, and N- [4- (3-chloro-benzene Group) -pyrimidin-2-yl] trifluoromethyl-phenyl) -amine is selected, in which the amine group is further substituted by R4, where R4 is as defined above. In yet another aspect, the present invention provides a compound of formula I, wherein -R1 is chloro '-R2 is hydrogen' -R3 is digas methyl and -R4 is hydrogen. In yet another aspect, the invention provides a compound of formula I, wherein

-R1為氯’ -R2為氮’ •R3為三氣甲基及 -R4 為式- C0·0-(CH2)2-N[(C2H50H)(CH3)]之基團。 本文中若未另外定義，芳基包括苯基。_素包括氟、氯 、溴。自烷基包括||化（C^)烷基，其中鹵化為一或多個 鹵素，較佳為三氟甲基。（c3.8)環烷基包括如（c3_6)環烷基 。胺基包括胺基、（Ci.4)烷胺基及二（Ci.4)烷胺基。胺烷基 包括胺（Cm)烷基，如（Cm)烷基胺（Ci.6)烷基、二（Cm) -11 - 200302728 ⑺-R1 is chlorine '-R2 is nitrogen' • R3 is a trisgasmethyl group and -R4 is a group of the formula -C0 · 0- (CH2) 2-N [(C2H50H) (CH3)]. Unless otherwise defined herein, aryl includes phenyl. Elements include fluorine, chlorine, and bromine. The self-alkyl group includes a || (C ^) alkyl group in which the halogenation is one or more halogens, preferably a trifluoromethyl group. (C3.8) Cycloalkyl includes, for example, (c3-6) cycloalkyl. The amine group includes an amine group, a (Ci.4) alkylamine group, and a bis (Ci.4) alkylamine group. Amine alkyl Including amine (Cm) alkyl, such as (Cm) alkylamine (Ci.6) alkyl, di (Cm) -11-200302728 ⑺

烷基胺（c^)烷基，較佳的是二取代的胺（<^_4)烷基胺 (Ci-4)烷基，如二甲基或二乙基胺（Chd烷基。羥烷基胺 基包括羥（Cu)烷基、羥（Ci-4)烷基胺（Cu)烷基，較佳的 是羥（CL3)烷基或羥（CbO烷基胺（Ci.2)烷基。胺基酸包括 所有天然及合成胺基酸，較佳為α -胺基酸，如丙胺酸、 苯基丙胺酸、甘胺酸、穀胺酸及賴胺酸。胺基酸包括一或 多個胺基酸，如二-或三胜肽。雜環基包括具有1至4個選 自Ν、Ο或S之雜原子的5或6員雜環系統。較佳的是，雜環 基為具有1或2個選自Ν或Ο之雜原子的5或6員雜環系統。 較佳的是ρ比咯淀、1，4 -氧氮陸圜及旅ρ井。Alkylamine (c ^) alkyl, preferably disubstituted amine (< ^ _ 4) alkylamine (Ci-4) alkyl, such as dimethyl or diethylamine (Chd alkyl. Hydroxy Alkylamine groups include hydroxy (Cu) alkyl, hydroxy (Ci-4) alkylamine (Cu) alkyl, preferably hydroxy (CL3) alkyl or hydroxy (CbOalkylamine (Ci.2) alkane Amino acids include all natural and synthetic amino acids, preferably alpha-amino acids such as alanine, phenylalanine, glycine, glutamic acid, and lysine. Amino acids include mono or Multiple amino acids, such as di- or tri-peptides. Heterocyclyls include 5 or 6-membered heterocyclic systems having 1 to 4 heteroatoms selected from N, 0 or S. Preferably, the heterocyclyl A 5- or 6-membered heterocyclic system having 1 or 2 heteroatoms selected from N or 0. Preferred are pirroline, 1,4-oxazoline, and bridging wells.

任何基團可為未經取代或經取代，如由有機化學中習見 基團取代，如包括由鹵素、鹵烷基、烷基羧基、烷氧基、 胺基、烷醯胺基、羥烷胺基、胺烷基胺基、烷基胺基、二 烷基胺基、具有5或6員環及1至4個選自Ν、Ο、S之雜原子 之雜環基、羥（〇^_4)烷基雜環基，其中雜環基具有5或6員 環及1至4個選自Ν、Ο、S之雜原子、羧基、（Cm)烷基羧 基、胺（Ci.4)烷基羧基選出之基團。 由本發明提供之化合物於下文中記為π本發明之化合物 π。本發明之化合物包括以任何形式之化合物，如以游離 形式、以鹽之形式、以溶解之形式及以鹽及溶解之形式。 本發明化合物之鹽包括醫藥上可接受之鹽，包括金屬鹽 或酸加成鹽。金屬鹽包括例如驗或驗土金屬鹽類；酸加成 鹽包括式I之化合物與酸包括之鹽，例如，包括無機及有 機酸，如，包括醫藥可接受之酸類，如氫氯酸、硫酸、曱 -12- (8)200302728Any group may be unsubstituted or substituted, such as by groups conventionally known in organic chemistry, including, for example, by halogen, haloalkyl, alkylcarboxy, alkoxy, amino, alkylamino, hydroxylalkylamine Group, amine alkylamino group, alkylamino group, dialkylamino group, heterocyclic group having 5 or 6-membered ring and 1 to 4 heteroatoms selected from N, 0, S, hydroxyl (〇 ^ _4 ) Alkylheterocyclyl, where the heterocyclyl has 5 or 6 membered rings and 1 to 4 heteroatoms selected from N, O, S, carboxy, (Cm) alkylcarboxy, amine (Ci.4) alkyl Carboxyl selected group. The compound provided by the present invention is hereinafter referred to as the compound π of the present invention. The compounds of the present invention include compounds in any form, such as in free form, in the form of a salt, in a dissolved form, and in a salt and dissolved form. Salts of the compounds of the present invention include pharmaceutically acceptable salts, including metal salts or acid addition salts. Metal salts include, for example, test or soil test metal salts; acid addition salts include compounds of formula I and salts of acids, for example, including inorganic and organic acids, such as including pharmaceutically acceptable acids, such as hydrochloric acid, sulfuric acid , 曱 -12- (8) 200302728

烷磺 可 相對 以溶 游離 本 構物含有 及其 物中 合物 物之本 據習 可基； 下列 酸、苯磺酸、對甲苯磺酸 、酒石酸。 將以游離形式的本發明化合物轉變成為以睡开， 應化合物；反之亦然。可將以游離 :形式之 ' n -Λι Μ 鹽 u 解形式的本發明化合物轉變成為以未溶解形^ ^及 形式或以鹽形式的相對應化合物；反之亦然又以 發明化合物可以異構物或其混合物之存在7如―風 、非鏡像異構物、順反異構物。本發明人光予異 σ物可你| j 不對稱碳原子，因此可以鏡像異構物、非浐 如 混合物之形式存在，如消旋體。如連接至： 文土奉發明化合 不對稱碳原子之取代基可於R-或於S_組熊， ^ I括其混 。本發明包括於任何異構物形式或於任何異構物混合 本發明化合物。 口 文中所述之任何化合物，如本發明化合物，可由如根 見方法或如本文說明之方法適當地製備。 將本發明化合物（其中胺基受苯基取代之哺淀；及苯 及氫取代）製備如根據如類似於習戽方法，較佳根據The alkanes are relatively soluble and free of the structural compounds and the basic compounds of the compounds; the following acids, benzenesulfonic acid, p-toluenesulfonic acid, and tartaric acid. Conversion of a compound of the invention in free form to a sleep-on-response compound; and vice versa. The compounds of the present invention in the free form of the 'n-ΛιM salt can be converted into the corresponding compounds in undissolved form and in the form of salts; and vice versa, the compounds of the invention can be isomers. Or its mixture 7 such as-wind, non-mirromeric isomers, cis-trans isomers. The inventors of the present invention presuppose that the σ can be asymmetric carbon atoms, so it can exist in the form of mirror image isomers, non-fluorenes such as mixtures, such as racemates. If connected to: Wen Tufeng invention compound Asymmetric carbon atom substituents can be in R- or S-bearing, including the mixture. The invention includes the compounds of the invention in any isomer form or mixed with any isomer. Any compound described orally, such as a compound of the invention, may be suitably prepared by a method such as that described herein or as described herein. The compound of the present invention (in which the amine group is substituted by phenyl groups; and benzene and hydrogen are substituted) is prepared according to, for example, similar to the Xi method, preferably based on

如定義 其中於式I、II及ΙΪΪ之化合物中，Ri、R2及R3為如上 ，及R4為Η ’及視情況進一步使得到的化合物與適當 -13- 200302728As defined wherein, among the compounds of formula I, II and I ，, Ri, R2 and R3 are as above, and R4 is 及 ', and the obtained compound is further appropriate as appropriate -13- 200302728

(9) 試劑反應以得到本發明化合物，如式i之化合物，其中r4 為如上定義，但非氫；如將式I之化合物（其中R4為Η而其 他取代基如上述定義） •與烷基碘在NaH存在下反應，以得到式I之化合物，其 中R4為燒基， -與溴-羥基烷反應以得到式I之化合物，其中R4為羥烷基，(9) The reaction of the reagent to obtain the compound of the present invention, such as a compound of formula i, wherein r4 is as defined above, but not hydrogen; for example, a compound of formula I (where R4 is Η and other substituents are as defined above) Reacting iodine in the presence of NaH to obtain a compound of formula I, wherein R4 is an alkyl group,-reacting with bromo-hydroxyalkane to obtain a compound of formula I, wherein R4 is a hydroxyalkyl group,

麵與式R5COOH之羧酸的醯鹵或酸酐反應（其中R5為如上 定義）以得到式I之化合物，其中r4為-co-r5，其中r5 為如上定義， -與光氣反應以得到式I之化合物，其中R4為-COC1，且進 一步將得到的化合物與下列式之化合物反應 a) R6-(CH2)m-OH，其中R6為如上定義及m為0，以得到 式I之化合物，其中R4為式-CO-(CH2)m-OR6i基團， 其中R6為如上定義及m為0，React with the halogen halide or anhydride of a carboxylic acid of formula R5COOH (where R5 is as defined above) to obtain a compound of formula I, where r4 is -co-r5, where r5 is as defined above, -react with phosgene to obtain formula I Compound, wherein R4 is -COC1, and the obtained compound is further reacted with a compound of the formula a) R6- (CH2) m-OH, wherein R6 is as defined above and m is 0 to obtain a compound of formula I, wherein R4 is a group of the formula -CO- (CH2) m-OR6i, where R6 is as defined above and m is 0,

b) R17-C0-0_(CH2)s_0H，其中R17及s為如上定義，以得 到式I之化合物，其中R4為式-C0-0-(CH2)s-0-C0-R17 之基團，其中Rl7及S為如上定義， C)N(Ri8Rl9)-(CH2)t-〇H ’ 其中 Ris、Rl9及 t為如上定義’ 以得到式I之化合物，其中R4為式-C0-0-(CH2)t-N(Ri8Rl9)之基團，其中Rl8、Rl9及t為如上定義， d)R20-(NH2)CH-CO-NH-(CH2)u-OH，其中 R20 及 u為如上 定義，以得到式I之化合物，其中r4為式 -CO-O-(CH2)u-NH-CO-CH(NH2)-R20之基團，其中 r20 及U為如上定義， -14-b) R17-C0-0_ (CH2) s_0H, wherein R17 and s are as defined above to obtain a compound of formula I, wherein R4 is a group of formula -C0-0- (CH2) s-0-C0-R17, Where R17 and S are as defined above, C) N (Ri8Rl9)-(CH2) t-OHH 'where Ris, R19 and t are as defined above to obtain a compound of formula I, where R4 is formula -C0-0- ( CH2) a group of tN (Ri8Rl9), where R18, R19 and t are as defined above, d) R20- (NH2) CH-CO-NH- (CH2) u-OH, where R20 and u are as defined above to obtain Compound of formula I, wherein r4 is a group of formula -CO-O- (CH2) u-NH-CO-CH (NH2) -R20, wherein r20 and U are as defined above, -14-

200302728 (ίο) e) R17-CO-NH-(CH2)w-OH，其中R”及w為如上定義，以 得到式i之化合物，其中R4為式-c〇-〇-(ch2)w-nh-co-r17 之基團，其中R17及w為如上定義’ -與式- c Ο - C1之化合物反應（其中R5為如上定義）以得到 式I之化合物，其中r4為式-c〇-R5之基團’其中R5為如上 定義， -與式尺6-〇-(<^2)111-(：〇-0：1之化合物反應（其中]^6為如上定 義）以得到式I之化合物，其中R4為式-CO-(CH2)m-〇R6之 基團，其中R6為如上定義， -與式R7-CO-CO-Cl之化合物反應（其中R7為如上定義）以 得到式I之化合物，其中R4為式- c〇-c〇-R7之基團，其中 R7為如上定義， -與式R8-0-CO-CO-C1之化合物反應（其中RS為如上定義） 以得到式I之化合物，其中R4為式-CO-CO-OR8之基團， 其中R8為如上定義， -與式（R9Ri〇)N-CO-C1之化合物反應（其中R9及R10為如上 定義）以得到式I之化合物，其中R4為式-c〇-N(R9RlG)2 基團，其中R9及Rio為如上定義’ -與式Rn-CO-CCHdn-CO-Cl之化合物反應（其中Rii及η為 如上定義）以得到式I之化合物，其中IU為式 -CO-(CH2)n-CO-Rn之基團，其中Rn及η為如上定義， -與式Rn-CO-CCHOo-CKCHRy-CO-Cl之化合物反應（其 中Rn、R16及〇為如上定義）以得到式I之化合物，其中化4 為式-CO-(CHR16)-0-(CH2)0-CO-Rn之基團，其中 R"、 200302728 (ii)200302728 (ίο) e) R17-CO-NH- (CH2) w-OH, where R "and w are as defined above to obtain a compound of formula i, wherein R4 is formula -c0-〇- (ch2) w- a group of nh-co-r17, wherein R17 and w are as defined above-reacting with a compound of formula-c 0-C1 (where R5 is as defined above) to obtain a compound of formula I, wherein r4 is formula -c〇- The group of R5 'wherein R5 is as defined above,-reacted with a compound of formula 6-〇-(< ^ 2) 111- (: 0-0: 1 (where) ^ 6 is as defined above) to obtain formula I Compound of which R4 is a group of the formula -CO- (CH2) m-〇R6, where R6 is as defined above,-reacting with a compound of formula R7-CO-CO-Cl (where R7 is as defined above) to obtain the formula Compound of I, wherein R4 is a group of formula -co-c0-R7, wherein R7 is as defined above,-reacting with a compound of formula R8-0-CO-CO-C1 (where RS is as defined above) to obtain Compound of formula I, wherein R4 is a group of formula -CO-CO-OR8, wherein R8 is as defined above,-reacting with a compound of formula (R9Ri〇) N-CO-C1 (where R9 and R10 are as defined above) with A compound of formula I is obtained, wherein R4 is a group of formula -co-N (R9R1G) 2, Where R9 and Rio are as defined above-react with a compound of formula Rn-CO-CCHdn-CO-Cl (where Rii and η are as defined above) to obtain a compound of formula I, where IU is formula -CO- (CH2) n -A group of CO-Rn, wherein Rn and η are as defined above,-reacting with a compound of formula Rn-CO-CCHOo-CKCHRy-CO-Cl (where Rn, R16 and 0 are as defined above) to obtain a compound of formula Where Hua 4 is a group of the formula -CO- (CHR16) -0- (CH2) 0-CO-Rn, where R ", 200302728 (ii)

Rl6及〇為如上定義， 與式 Ri6-(CH2)r — 0-(CH2)q-0-(CH2)P-CO-Cl之化合物反 應（其中R i 6、r、p及q為如上定義）以得到式I之化合物， 其中 R4為式 _CO-(CH2)p-0-(CH2)q-〇-(CH2)r-Ri6之基團， 其中R16、r、p及q為如上定義， -與式C1-OC-(CH2)v-CO-C1之化合物反應以得到式1之化 合物，其中R4為式-CO-(CH2)v-CO-C1之基團’並進一步 將得到的化合物與胺基酸、胺基酸單（Ci-6)、庑基酯、胺基 酸二（Ci-6)烷基酯反應或與一級或二級胺反應’视情況含 有額外的胺基基團，以得到式I之化合物’其中R4為式 -CO-(CH2)v-CO-胺基酸、-C0_(CH2)v-C0-胺基酸單（c1-6) 烷基酯或-CO-(CH2)v-CO-胺基酸二（Ci-6)烷基酯之基團 ，而v為1至6，較佳為1至5。 式I之化合物（其中R4為Η而其他取代基為如上定義）以 適當試劑（其中R4為如上定義，但非氫）而得到式I之化合 物之反應為烷化或醯化反應，可由適當如類似於習見方法 或如上述適當地進行。於此類反應中，取代基（如羥基或 胺基基團）可於反應前保護並於反應期間或之後去保護。 於另一方面，本發明提供式Ϊ化合物之製造方法，包含 有反應式II化合物（其中I為如上定義而ALK代表燒基或 環坑基）與式111化合物（其中r2及r3為如上定義），而得到 式I之化合物，其中I、R2& R3為如上定義，而r4為氫， 視情況如烷化或醯化得到的化合物，及視需要去保護基團 ，以得到式I之化合物，其中Ri、r2及R3為如上定義，而 200302728R16 and 0 are as defined above, and react with compounds of the formula Ri6- (CH2) r — 0- (CH2) q-0- (CH2) P-CO-Cl (where R i 6, r, p, and q are as defined above) ) To obtain a compound of formula I, wherein R4 is a group of formula -CO- (CH2) p-0- (CH2) q-〇- (CH2) r-Ri6, wherein R16, r, p and q are as defined above , -React with a compound of formula C1-OC- (CH2) v-CO-C1 to obtain a compound of formula 1, wherein R4 is a group of formula -CO- (CH2) v-CO-C1 'and further obtain the Compound reacts with amino acid, amino mono (Ci-6), fluorenyl ester, amino di (Ci-6) alkyl ester, or reacts with primary or secondary amines' Contains additional amine groups as appropriate Group to obtain a compound of formula I where R4 is a formula -CO- (CH2) v-CO-amino acid, -C0_ (CH2) v-C0-amino acid mono (c1-6) alkyl ester, or- A group of CO- (CH2) v-CO-amino acid di (Ci-6) alkyl ester, and v is 1 to 6, preferably 1 to 5. Compounds of formula I (where R4 is fluorene and other substituents are as defined above) The reaction to obtain compounds of formula I with an appropriate reagent (where R4 is as defined above, but not hydrogen) is an alkylation or tritiation reaction. Similar to the conventional method or appropriately as described above. In such reactions, substituents (such as hydroxyl or amino groups) can be protected before the reaction and deprotected during or after the reaction. In another aspect, the present invention provides a method for producing a compound of formula (I), which comprises a compound of formula II (where I is as defined above and ALK represents a alkynyl or a ring pit group) and a compound of formula 111 (where r2 and r3 are as defined above) To obtain a compound of formula I, wherein I, R2 & R3 are as defined above, and r4 is hydrogen, and a compound obtained by alkylation or halogenation as appropriate, and a deprotection group, if necessary, to obtain a compound of formula I, Where Ri, r2, and R3 are as defined above, and 200302728

(12) R4為如上足義，但非氫，並由反應混合物中分離得到的式 I化合物。 本文中所述之任何化合物，如本發明化合物，可由如根 據習見方法或如本文說明之方法適當地製備。式π及式ΙΠ 之化合物為已知或可由如根據習見方法或本文說明之方 法得到。 本發明化合物呈現試管内及活體内藥理活性且因而有 用於作為醫藥： 在過敏反應的過程中，如在氣管中，τ•辅助第二類細胞 (Th2細胞）自原生Τ_細胞母體伴隨由樹突狀細胞（DC， dendritic cell)呈現之過敏原刺激下在Th2細胞激素（ cytokine) IL-4存在中產生.此等Th2細胞引發肺部複雜 發炎反應導致過敏性氣喘病的開始及惡化。由此等Th2 細胞產生之細胞激素（其包括如IL-4，IL-5jl-10及IL-13) 調節前-發炎作用細胞如嗜伊紅血球、嗜鹼細胞及累積於 肺部的巨細胞（mast cell)之擴張。 此外，IL-4及IL-3引發B細胞產生IgE。igE對巨細胞及 嗜驗細胞上高親合力IgE受體的結合，之後受過敏原交聯 ，造成前-發炎細胞的活化及過敏發炎傳遞物的釋放。 基於此等觀察，吾人期望抑制Th2細胞調節的過敏發炎 反應及對IgE產生之效果兩者可提供一個新穎的方式有效 地干擾過敏性氣喘病及其他過敏性疾病如過敏性皮膚炎 、過敏性結膜炎及過敏性鼻炎。 吾人已發現本發明化合物可作用A人 ^ J讣用為人體Dc功能的凋即 -17- 200302728(12) R4 is as defined above, but is not hydrogen, and is a compound of formula I isolated from the reaction mixture. Any of the compounds described herein, such as the compounds of the invention, can be suitably prepared by conventional methods or methods as described herein. Compounds of formula π and formula II are known or can be obtained as per conventional methods or methods described herein. The compounds of the present invention exhibit pharmacological activity in vitro and in vivo and are therefore useful as medicine: During the process of allergic reactions, such as in the trachea, τ • helper type 2 cells (Th2 cells) are derived from the native T_cell parent and are accompanied by dendritic Allergens presented by dendritic cells (DCs) are produced in the presence of Th2 cytokine IL-4 under stimulation of these allergens. These Th2 cells trigger a complex inflammatory response in the lungs that leads to the onset and deterioration of allergic asthma. The cytokines produced by these Th2 cells (which include, for example, IL-4, IL-5jl-10, and IL-13) regulate pre-inflammatory cells such as eosinophils, basophils, and giant cells that accumulate in the lungs ( mast cell) expansion. In addition, IL-4 and IL-3 trigger B cells to produce IgE. igE binds to the high-affinity IgE receptors on giant cells and psychrophils, and is subsequently cross-linked by allergens, causing the activation of pre-inflammatory cells and the release of allergic inflammatory mediators. Based on these observations, I hope that both the inhibition of Th2 cell-regulated allergic inflammation and the effect on IgE can provide a novel way to effectively interfere with allergic asthma and other allergic diseases such as allergic dermatitis, allergic conjunctivitis And allergic rhinitis. We have found that the compounds of the present invention can act on human A ^ J 讣 for the function of human Dc -17- 200302728

體。已知DC細胞表面分子對於與原生τ'細胞母體的交互 作用很重要，如在以本發明化合物處理時可將 CD86，CD83, CD25及HLA第二類抗原減少於人體單核白 血球衍生的樹突狀細胞表面上。類似地’成熟〇(：之1]：_6 分泌可受本發明化合物抑制。經化合物處理之樹突狀細胞 顯示出受損能力於刺激增殖及原生CD4_自體移植τ細胞 的細胞激素產生。body. It is known that DC cell surface molecules are important for interaction with native τ 'cell mothers. For example, when treated with the compounds of the present invention, CD86, CD83, CD25 and HLA type II antigens can be reduced to human monocyte-derived dendritic cells. Cells on the surface. Similarly, 'mature 0 (:-1]:-6 secretion can be inhibited by the compounds of the present invention. Compound-treated dendritic cells show impaired ability to stimulate proliferation and cytokine production by native CD4_ autotransplanted τ cells.

此外，吾人已發現本發明化合物可作用為IgE合成之專 一抑制劑。在組織或口服施用時本發明之化合物可抑制免 疫血球素合成，特別是B淋巴球中免疫血球素E的合成， 即本發明之化合物可呈現同種型專一性。再者，吾人已發 現本發明化合物於阻止IgE合成所需濃度以下之濃度不可 抑制B細胞增殖。 此等活性可於下列試驗中顯現。溫度單位為t且未經校 正。使用下列縮寫：In addition, we have found that the compounds of the present invention can act as specific inhibitors of IgE synthesis. The compound of the present invention can inhibit immunoglobulin synthesis, especially the synthesis of immunohemoglobin E in B lymphocytes, when tissue or oral administration, that is, the compound of the present invention can exhibit isotype specificity. Furthermore, we have found that the concentration of the compound of the present invention below the concentration required to prevent IgE synthesis cannot inhibit B cell proliferation. These activities can be seen in the following tests. Temperature units are t and uncorrected. Use the following abbreviations:

DC 樹突狀細胞（Dendritic cell) ELISA 酵素連結免疫吸附試驗（enzyme-linked immunosorbent assay) FACS 螢光活化細胞分類（fluorescence-activated cell sorting) FCS 胎牛血清（fetal calf serum) GM-CSF有粒細胞巨嗟菌體·菌落刺激因子（granulocyte macrophage-colony stimulation factor)DC Dendritic cells ELISA enzyme-linked immunosorbent assay FACS fluorescence-activated cell sorting FCS fetal calf serum GM-CSF granulocytes Granulocyte macrophage-colony stimulation factor

IgE 免疫血球素 E(immunoglobulin E) -18 - 200302728IgE immunoglobulin E -18-200302728

(14) IL-4 白細胞介素 _4(interleukin-4) IL-5 白細胞介素-5(interleukin-5) IL-6 白細胞介素-6(interleukin-6) IL-10 白細胞介素-lO(interleukin-lO) IMDM Iscove’s modified Dulbecco medium KLH 鎖眼帽貝血藍蛋白（keyhole limpet hemocyanin)(14) IL-4 interleukin-4 IL-5 interleukin-5 IL-6 interleukin-6 IL-10 interleukin-10 (interleukin-lO) IMDM Iscove's modified Dulbecco medium KLH keyhole limpet hemocyanin

Mo-DC 單核白血球衍生的樹突狀細胞（monocyte derived dendritic cells) PBMC 周邊血液單核細胞（peripheral blood mononuclear cells) SRBC 羊紅血球細胞（sheep red blood cells) RT 室溫（room temperature)Mo-DC monocyte derived dendritic cells PBMC peripheral blood mononuclear cells SRBC sheep red blood cells RT room temperature

Th T輔助細胞（T helper cell)Th T helper cell

Th2 T輔助第二類細胞（T helper cell type 2) 1.同種型專一性： 抑制由細胞激素及抗-CD40抗體刺激一級人體B淋巴球引 發之免疫血球素合成 自正常人體脾臟將單核細胞純化。由FACS分析中以 CD 19表現判定形成的細胞懸浮液含有50-70%B-淋巴球。 利用96-孔圓底多孔滴定盤（Costar)將5 X 104個脾臟細胞 於IMDM中製成最終體積為200微升/孔。在以測試化合物 預先培養1小時後，將細胞於37°C以供應5%(：02之空氣中 ，在50 ng/ml IL-4及5 00 ng/ml抗- CD40抗體存在中培養9 天，以引發IgE產生。將培養細胞上層液收集並以標準同 -19- 200302728Th2 T helper cell type 2 1. Isotype specificity: Inhibits the synthesis of immunohemoglobin induced by cytokines and anti-CD40 antibodies in primary human B lymphocytes from normal human spleen and monocytes purification. The cell suspension formed by CD 19 performance as determined by FACS analysis contained 50-70% B-lymphocytes. A 96-well round-bottomed multi-well titer plate (Costar) was used to prepare 5 X 104 spleen cells in IMDM to a final volume of 200 µl / well. After pre-incubating with the test compound for 1 hour, the cells were cultured at 37 ° C to supply 5% (: 02 air) in the presence of 50 ng / ml IL-4 and 500 ng / ml anti-CD40 antibody for 9 days. In order to trigger the production of IgE. The supernatant of the cultured cells was collected and the standard was the same as -19-200302728.

(15) 種型專一三明治ELISA方法定量IgE。對於IgG合成的引發 ，將細胞以100ng/ml IL-10及500 ng/ml抗- CD40抗體培養 相同期間，之後藉同種型專一 ELISA將細胞上層液中的 IgG定量。 於此等測試中，本發明化合物抑制IgE生產優於IgG。 2 . B ·細胞增殖: 根據 M.S· Weiner等人於 Blood 42(1973)939，藉由以 S RB C -玫瑰形細胞集結T細胞法去除污染的τ細胞，將正常 人體B _淋巴球自扁桃腺純化。由f a C S分析中以C D 1 9表現 判定形成的B -細胞為大於9 5 %純度。利用9 6 -孔圓底多孔 滴定盤（Costar)將1 X 1〇5個脾臟細胞於iMDM中製成最終 體積為2 0 0微升/孔。在以測試化合物預先培養1小時後， 以50 ng/ml IL-4及5 00 ng/ml抗-CD4〇抗體引發細胞增殖。 於37 C以供應5%C〇2之空氣中培養4天後，將1 #ci氚化胸 腺喊淀核甘加入並將細胞培養約16小時。將細胞收集於硝 化纖維素濾紙上並由液體閃爍計數將DNA_結合放射線定 量。 於此等測試中，本發明化合物抑制IL_4及抗_CD4〇抗體 調節之B-細胞增殖高於阻止IgE合成所需濃度。 3 . 細胞表面標諸之詷節； 藉由淘析或藉由利用市售配套組合（Miltenyi)反面選擇 PBMC，將人體周邊血液單核細胞製備。由facs, cdi4 染色證實純度，形成的單核細胞總數常規上〉97%對cm4 呈陽性。將單核細胞以3 X 1〇6個細胞/孔植於6孔盤中，於 -20-(15) IgE quantification by type-specific sandwich ELISA. For the initiation of IgG synthesis, cells were cultured with 100 ng / ml IL-10 and 500 ng / ml anti-CD40 antibody for the same period, and then IgG in the cell supernatant was quantified by isotype specific ELISA. In these tests, the compounds of the invention inhibit IgE production better than IgG. 2. B. Cell Proliferation: According to MS Weiner et al. In Blood 42 (1973) 939, by removing the contaminated τ cells by the S RB C-rosette cell assembly T cell method, normal human B_lymphocytes are derived from almond Gland purification. The B-cells formed were judged to be C D 1 9 in the f a C S analysis and were more than 95% pure. 1 × 105 spleen cells were made in iMDM using a 96-well round bottom multi-well titer plate (Costar) to make a final volume of 200 μl / well. After incubation with the test compound for 1 hour in advance, cell proliferation was induced with 50 ng / ml IL-4 and 500 ng / ml anti-CD40 antibody. After culturing at 37 C for 4 days in air supplied with 5% CO 2, 1 #ci tritiated thymocytes were added and the cells were cultured for about 16 hours. Cells were collected on nitrocellulose filter paper and DNA_binding radiation was quantified by liquid scintillation counting. In these tests, the compounds of the invention inhibited IL-4 and anti-CD4O-regulated B-cell proliferation at a higher concentration than required to prevent IgE synthesis. 3. The cell surface is labeled with a knot; by elutriation or by using a commercially available kit (Miltenyi) to select PBMC, the peripheral blood mononuclear cells of the human body are prepared. Purity was confirmed by facs, cdi4 staining, and the total number of monocytes formed was routinely> 97% positive for cm4. Mononuclear cells were seeded in 6-well dishes at 3 × 106 cells / well at -20-

200302728 (16) 5ml IMDM培養液補充1%FCS、鏈黴素及穀胺醯胺。藉由 加入40ng/ml IL-4及15ng/ml GM-CSF，在測試化合物無或 有的條件下6天將不成熟的Μ 〇 - D C的產生引發。頭兩天之 後，將一半體積以新鮮培養液、細胞激素及適當化合物替 換。在培養第6天，由卩八08染色將€〇86及111^人-〇11的細胞 表面表現量測量。200302728 (16) 5ml IMDM medium was supplemented with 1% FCS, streptomycin and glutamine. By adding 40 ng / ml IL-4 and 15 ng / ml GM-CSF, the production of immature MO-DC was initiated in the absence or presence of the test compound for 6 days. After the first two days, half of the volume was replaced with fresh medium, cytokines and appropriate compounds. On the 6th day of culture, the cell surface expression of € 86 and 111 ^ human-〇11 was measured by 卩 08 08 staining.

以 100ng/ml LPS(Sigma)或由含有 20ng/ml GM-CSF、 100U/ml IFN- r、20U/ml TNF-α 及 4/zg/ml交聯的抗- CD40 單株抗體之混合物活化不成熟D C 2 4小時而引發D C之熟 化。而後，由FACS將CD83及CD25的細胞表面表現量定量。 於此等測試中，本發明化合物抑制CD86、HLA-DR、 CD83及CD25的細胞表面表現量。 4.PC調節抗原專一自體移植胞刺激試驗：Activated with 100ng / ml LPS (Sigma) or a mixture of cross-linked anti-CD40 monoclonal antibodies containing 20ng / ml GM-CSF, 100U / ml IFN-r, 20U / ml TNF-α, and 4 / zg / ml Mature DC 2 for 4 hours to cause DC maturation. Then, the cell surface expression of CD83 and CD25 was quantified by FACS. In these tests, the compounds of the invention inhibit the cell surface expression of CD86, HLA-DR, CD83 and CD25. 4. PC-regulated antigen-specific autotransplantation cell stimulation test:

在測試化合物無或有的條件下將不成熟的Mo-DC產生 。而後，以100 /zg/ml KLH將細胞衝擊隔夜，而後與自體 移植CD4·T-細胞共同培養9天以於測試化合物無或有的 條件下引發主要T-細胞反應。細胞清洗後，將原始的τ-細胞以新鮮KLH衝擊的DC以不同T/DC比例重新刺激3天 不添加化合物。在最後丨6小時，將i #ci氚化胸腺嘧啶核 甘加入。將細胞收集於硝化纖維素濾紙上並由液體閃爍計 數將D N A -結合放射線定量。 於此等測試中，本發明化合物抑制DC調節之T細胞增殖。 5 · TjJgLB細跑敫素製造: 由DC/Τ細胞重新刺激培養（見上述）之上層液於48小時Immature Mo-DC is produced in the absence or presence of the test compound. Then, the cells were impacted overnight with 100 / zg / ml KLH, and then co-cultured with autotransplanted CD4 · T-cells for 9 days to elicit a major T-cell response in the absence or presence of the test compound. After the cells were washed, the original τ-cells were restimulated with fresh KLH shock DC at different T / DC ratios for 3 days without compound addition. In the last 6 hours, i #ci 氚 thymidine was added. Cells were collected on nitrocellulose filter paper and DN A-bound radiation was quantified by liquid scintillation counting. In these tests, the compounds of the invention inhibit DC-regulated T cell proliferation. 5 · Manufactured by TjJgLB serotonin: Re-stimulate the culture supernatant (see above) from DC / T cells for 48 hours

-2K 200302728-2K 200302728

(17) 後取出並利用市售配套組合以ELISA定量GM-CSF及IL-2。 於此等測試中，本發明化合物抑制DC調節之T-細胞細 胞激素製造。 6·本發—明化合物於血漿中安定性之測定··(17) Take out and quantify GM-CSF and IL-2 by ELISA using a commercial combination. In these tests, the compounds of the invention inhibit DC-regulated T-cell cytokine production. 6 · Benfa—Determination of stability of bright compounds in plasma ··

防凝集血液由人體自願者及由Balb/c小老鼠取得。將得 到的血於室溫以1 3，0 0 0 rp m離心4分鐘而得到血漿。將測 試化合物（即本發明化合物）（1 1〇 母液於DMSO或水 )加入1 ml血漿中。將樣品於37培養。在不同時間點， 將100 //1自該樣品中取出。將内標（5山之1〇〇 Vg/W内標準 化合物於甲醇中之溶液），之後加入3 〇 〇 /^甲醇（視需要， 或丙腈或丙腈/1MHC1)。將樣品以13,000 rpm離心5分鐘。 為了分析，將得到的上層液50 //1注入HPLC系統（HP 1 090)，其裝有 Hypersil BDS C-8 管柱（5 //m，250 X 4.6 mm 加上前管柱（1 0 X 4 · 6 mm)。將管柱於5 5 °C及流速丄5 ml/miri以丙腈及10 mM (NH4)2S04，ΡΗ 2·7之混合物沖提 :使用的混合物之丙腈含量對不同物質為55-65〇/〇範圍内。 特定化合物之分析可能需要不同HPLC系統，如管柱：Anticoagulated blood was obtained from human volunteers and from Balb / c mice. The obtained blood was centrifuged at 13,000 rpm for 4 minutes at room temperature to obtain plasma. The test compound (ie, the compound of the present invention) (1 10 stock solution in DMSO or water) was added to 1 ml of plasma. The samples were incubated at 37. At different time points, 100 // 1 was taken from the sample. An internal standard (a solution of 100 Vg / W of an internal standard compound in 5 mols in methanol) was added, followed by 3,000 / methanol (as needed, or propionitrile or propionitrile / 1MHC1). The samples were centrifuged at 13,000 rpm for 5 minutes. For analysis, the resulting supernatant 50 // 1 was injected into an HPLC system (HP 1 090), which was fitted with a Hypersil BDS C-8 column (5 // m, 250 X 4.6 mm plus a front column (1 0 X 4 · 6 mm). Extract the column at 5 5 ° C and a flow rate of 5 ml / miri with a mixture of propionitrile and 10 mM (NH4) 2S04, P 2 · 7: the propionitrile content of the mixture used is different. The substance is in the range of 55-65 0 / 〇. Analysis of specific compounds may require different HPLC systems, such as column:

Zorbax Extend C18(3.5 /zm，150 X 4·6 mm);前管柱： Hypersil BDS，C-8 (5/m，10X4.6 mm) ; RT ;溶劑之丙腈 含量：6 5 %。 UV偵測於277 nm進行。為了校正，將血漿樣品摻入式j 化合物其中R4為氫，或式I化合物其中r4為如上定義，但 非氫；兩者皆於〇 · 5至20 /zM之範圍内，及内標。利用此等 校正設定將絕對濃度計算。 200302728Zorbax Extend C18 (3.5 / zm, 150 X 4.6 mm); front column: Hypersil BDS, C-8 (5 / m, 10X4.6 mm); RT; propionitrile content of solvent: 65%. UV detection was performed at 277 nm. For calibration, a plasma sample is incorporated into a compound of formula j where R4 is hydrogen, or a compound of formula I where r4 is as defined above, but not hydrogen; both are in the range of 0.5 to 20 / zM, and the internal standard. With these correction settings, the absolute density is calculated. 200302728

Mmmm (18) 於此等測定測試中，吾人已發現式I化合物其中R4為如 上定義，但非氫者，於血漿中具有比式I化合物其中R4為 氫較低安定性。由此可假設式I化合物其中r4為如上定義 · ，但非氫者可視為式I化合物其中R4為氫的前藥。另一方 . 面，式I化合物其中R4為氫可建立高度活性原理，如可建 立發現於試管内及活體内之本發明化合物驚人活性的基 本構造。因此可將式I化合物其中r4為氫視為具有正常藥 物結構的彼等化合物。 Φ 本發明化合物顯示良好溶解度及良好血漿濃度於如口 服後。 所以，本發明化合物有用於作為D C功用的調節劑及免 疫血球素合成之抑制劑，特別是I g E合成的抑制劑，並有 用於治療I g E調節的疾病，特別是I g E調節之過敏疾病，如 由IgE表現調節之疾病，如過敏性皮膚炎（特別是孩童）、 蓴麻疹（特別是急性蓴麻疹）、過敏性氣喘、過敏性鼻炎、 食物過敏、過敏性結膜炎、花粉症、天皰瘡及工業的敏化 _ 作用。此外，此等化合物有用於其他疾病，其中發炎情況 扮演主要病理角色，如自體免疫疾病（如全身紅斑性狼瘡 、牛皮癖及風濕性關節炎）及胃腸疾病（如克隆氏症（ C r 〇 h n s d i s e a s e ))及移植的慢性排斥。 · 於另一方面，本發明提供一種胺類之用途，其經 β -經苯基取代之嘧啶；及 -苯基；及 -第三種取代基， -23- (19) (19)200302728Mmmm (18) In these assays, we have found that compounds of formula I in which R4 is as defined above, but non-hydrogen, have lower stability in plasma than compounds of formula I in which R4 is hydrogen. Therefore, it can be assumed that the compound of formula I in which r4 is as defined above, but the non-hydrogen can be regarded as a prodrug of the compound of formula I in which R4 is hydrogen. On the other hand, the compound of formula I in which R4 is hydrogen can establish a highly active principle. For example, it can establish the basic structure of the amazing activity of the compound of the present invention found in test tubes and in vivo. Compounds of formula I where r4 is hydrogen can therefore be regarded as their compounds having a normal drug structure. Φ The compound of the present invention shows good solubility and good plasma concentration after oral administration. Therefore, the compounds of the present invention are useful as modulators of DC function and inhibitors of immunohemoglobin synthesis, especially inhibitors of I g E synthesis, and are used for treating diseases regulated by I g E, especially those regulated by I g E Allergic diseases, such as those regulated by IgE manifestations, such as allergic dermatitis (especially children), measles (especially acute measles), allergic asthma, allergic rhinitis, food allergies, allergic conjunctivitis, hay fever, Pemphigus and industrial sensitization_. In addition, these compounds are useful in other diseases where inflammation plays a major pathological role, such as autoimmune diseases (such as systemic lupus erythematosus, psoriasis, and rheumatoid arthritis) and gastrointestinal diseases (such as Crohn's disease (C r 〇 〇 hnsdisease)) and chronic rejection of transplantation. · In another aspect, the present invention provides the use of an amine, which is β-pyrimidine substituted with phenyl; and -phenyl; and-a third substituent, -23- (19) (19) 200302728

取代，如本發明之化合物，#治療㈣合成調節的疾病、 自組免疫疾病、胃腸疾病及移植的慢性排斥之藥劑製備中。 在較佳的方面中，本發明提供式I化合物之用途，其中 取=基1^至r4為如上定義，於治療igE合成調#的疾病、 自體免疫疾病、胃腸疾病及移植的慢性排斥之藥劑製備中。 對於上述用途’當然視如使用的特定化合物、施用形式 :希望的治療而定’所使用的劑量將不同。然1¾，當將化 一、每天、力1 mg/kg至約30 mg/kg動物重量之劑量施用 ’適當地分配每天2至4次給？，一般可得到滿意的結果。 對於大部分較大哺乳類，總每日劑量為約至約 mg，方便地施用，你丨古、土 、 〗如以回達一天4次分開劑量或以延遲 形式施用。單位密I丨吾耶斗、 里7式包含’例如，約1 7 · 5 m g至約1 〇 〇 〇 m g化合物與至少—插»曲 種固m或液體醫藥可接受賦形劑，如 載體或稀釋劑，之混合物。 、”、本發明之化合物以類似於已知標準如血漿糖成 激^及杬組織胺用於此類適應症之方式服用。可將其病 見醫：上可接受的載體及稀釋劑及視情況另外的賦开 二先奶口 ，並如以口服服用，以藥片、膠囊形式，或： ° '、局部施用’如以習見形式，如煙霧劑、軟膏或孚 t服或靜脈 >王射。當然物質之濃度不同，如視施月 δ物、理想的治療及形式的天性而定。然而，—般, 於局部塗体形式以濃度約0·05重量％至約5重量 約。:重量%至約1重量”得到滿意的結果。 於另—方面，本發明提供本發明化合物之用途於製子 -24- 200302728 (20) 療1gE-調節疾病，如由IgE表現調節之疾病、自體免疫疾 病、胃腸疾病及慢性移植排斥之藥劑。 用於治療IgE-調節疾病、自體免疫疾病、胃腸疾病及慢 ‘ 性移植排斥之醫藥組合物可由混合本發明化合物與至少 · 一種醫藥可接受的賦形劑，如載體或稀釋劑，而製備。 於另一方面，本發明提供治療IgE_調節疾病、自體免疫 疾病、胃腸疾病及慢性移植排斥之方法，包含有施用治療 有效置之本發明化合物（如以醫藥組合物形式）至需要如 _ 此治療之對象。 本發明之化合物可良好耐受，如可根據習見方法測定。 本發明化合物可具有有利的醫學製劑性質，如於許多溶劑 中有良好溶解度。 於另一方面，本發明提供本發明化合物用於作為藥劑， 特別是於製備IgE調節之疾病、自體免疫疾病、胃腸疾病 及慢性移植排斥之適應症。 、本發明化合物可以醫藥可接受的鹽類形式施用（如酸加 _ =取或金屬鹽）、或以游離形式、视情況以溶解形式。以 二^式之本發明化合物呈現如同以游離形式之本發明化 口物相同次方活性；視情況以溶解形式。 万；另一万面，本發明提供一種醫藥組合物，包含有本發 ， 明化合物與至少一種醫藥可接受職形劑（如載體或稀釋劑 )結合。根據習見方法可將此組合物製造。 據本發明本身，或與一或多種其他醫藥活性劑組合， U有用於治療1 gE -調節疾病，特別是IgE調節之過敏疾病 -25 - 200302728Instead, such as the compounds of the present invention, # in the preparation of pharmaceuticals for the treatment of chronic diseases such as dysregulation, autoimmune diseases, gastrointestinal diseases and transplantation. In a preferred aspect, the present invention provides the use of a compound of formula I, wherein the groups 1 to 4 are as defined above for the treatment of igE synthesis-modulated diseases, autoimmune diseases, gastrointestinal diseases, and chronic rejection of transplantation. Preparation of pharmaceuticals. For the above-mentioned use, the dosage used will, of course, vary depending on the specific compound used, the form of administration: depending on the desired treatment. Of course, 1¾, when administering a daily dose of 1 mg / kg to about 30 mg / kg of animal weight, ‘appropriately distribute 2 to 4 times a day? , Generally can get satisfactory results. For most larger mammals, the total daily dose is from about to about mg, and is conveniently administered as if it were administered in divided doses up to 4 times a day or in a delayed form. The unit formula I is contained in Formula 7 where, for example, about 17.5 mg to about 10,000 mg of a compound with at least—insert acetone or a liquid pharmaceutically acceptable excipient, such as a carrier or Thinner, mixture. The compound of the present invention is administered in a manner similar to known standards such as plasma glucose formation and histamine for such indications. The disease can be seen by a doctor: an acceptable carrier and diluent, and Circumstances are additionally given to Erxian milk mouth, and if taken orally, in the form of tablets, capsules, or: ° ', topical administration' as in the conventional form, such as aerosols, ointments or fu or clothing > Wang She .Of course, the concentration of the substance is different, depending on the nature of the application of the δ substance, the ideal treatment and the form. However, in general, in the form of a topical body, the concentration is about 0.05% by weight to about 5% by weight .: Weight % To about 1 weight "gives satisfactory results. In another aspect, the present invention provides a compound of the present invention for use in the formulation-24- 200302728 (20) for the treatment of 1gE-modulated diseases, such as diseases regulated by IgE performance, autoimmune diseases, gastrointestinal diseases and chronic transplant rejection . A pharmaceutical composition for treating IgE-modulated diseases, autoimmune diseases, gastrointestinal diseases and chronic transplant rejection can be prepared by mixing the compound of the present invention with at least one pharmaceutically acceptable excipient, such as a carrier or diluent. . In another aspect, the present invention provides a method for treating IgE-modulating diseases, autoimmune diseases, gastrointestinal diseases, and chronic transplant rejection, comprising administering a therapeutically effective compound of the invention (for example, in the form of a pharmaceutical composition) to a patient in need. The subject of this treatment. The compounds of the present invention are well tolerated and can be determined, for example, according to conventional methods. The compounds of the invention may have advantageous medical formulation properties, such as good solubility in many solvents. In another aspect, the invention provides a compound of the invention for use as a medicament, particularly for the preparation of IgE-regulated diseases, autoimmune diseases, gastrointestinal diseases, and indications for chronic transplant rejection. 2. The compound of the present invention can be administered in the form of a pharmaceutically acceptable salt (such as an acid plus a salt or a metal salt), or in a free form and optionally in a dissolved form. The compound of the present invention in the formula (2) exhibits the same power as the chelate of the present invention in a free form; optionally in a dissolved form. In another aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention in combination with at least one pharmaceutically acceptable agent (such as a carrier or diluent). This composition can be made according to conventional methods. According to the invention itself, or in combination with one or more other pharmaceutically active agents, U is useful for the treatment of 1 gE-regulated diseases, especially allergic diseases regulated by IgE -25-200302728

(21) ’如由I gE表現調節之疾病，如異位性皮膚炎（特別是孩童 )、蓴麻療（特別是急性蓴麻疹）、過敏性氣喘、過敏性鼻 炎、食物過敏、過敏性結膜炎、花粉熱、大皰性類天皰瘡 及工業敏化作用。此外，此等化合物適用於其他疾病其中 發炎情況扮演主要病理角色，如自體免疫疾病（如全身紅 斑性狼瘡、牛皮癬及風溼性關節炎）及胃腸疾病（如克隆氏 症（Crohns disease ))及慢性移植排斥。此類其他醫藥活 性劑包括如類固醇、抗組織胺、子囊黴素（ascomycins)、 ASM981、雷帕黴素（rapamycins)。 組合物包括固定組合（其中兩或多種醫藥活性劑於相同 配方中）、配套元件（其中於分開配方中的兩或多種醫藥活 性劑於一個相同包裝中販賣，如與一起服用之指示）、及 自由組合（其中將醫藥活性劑分開包裝，但給予同時或順 序服用之指示）。 於另一方面，本發明提供一種醫藥組合物，包含有本發 明化合物作為活性成份與一或多種其他醫藥活性劑組合 ，如包括固定組合、配套元件及自由組合，其中其他醫藥 活性劑為自如.類固醇、抗組織胺、子囊黴素（asc〇mycins) 、ASM981、雷帕黴素（rapamycins)組成之族群選出。 於下列說明本發明之實例中，所提溫度單位為攝氏溫度 且未經校正。於1 Η · N M R中化學位移以德爾塔單位給予、j 值單位為Hz。使用下列縮寫： m.p.溶點 RT室溫 -26- 200302728(21) 'If diseases are regulated by I gE performance, such as atopic dermatitis (especially children), ramie therapy (especially acute rash measles), allergic asthma, allergic rhinitis, food allergies, allergic conjunctivitis , Hay fever, bullous pemphigoid and industrial sensitization. In addition, these compounds are suitable for other diseases where inflammation plays a major pathological role, such as autoimmune diseases (such as systemic lupus erythematosus, psoriasis, and rheumatoid arthritis) and gastrointestinal diseases (such as Crohns disease) and Chronic transplant rejection. Such other pharmaceutically active agents include, for example, steroids, antihistamines, ascomycins, ASM981, rapamycins. The composition includes a fixed combination (in which two or more pharmaceutically active agents are in the same formulation), a kit (in which two or more pharmaceutically active agents in separate formulations are sold in the same package, as indicated by taking with them), and Free combination (where the pharmaceutically active agents are packaged separately, but instructions are given for simultaneous or sequential administration). In another aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention as an active ingredient in combination with one or more other pharmaceutically active agents, such as including fixed combinations, supporting components and free combinations, wherein other pharmaceutically active agents are free. The group consisting of steroids, antihistamines, ascomycins, ASM981, and rapamycins was selected. In the following examples illustrating the invention, the temperature units are given in degrees Celsius and are uncorrected. The chemical shift in 1 Η · N M R is given in delta units and the unit of j value is Hz. The following abbreviations are used: m.p. melting point RT room temperature -26- 200302728

(22) br·寬 實施方式 實例1 N-[4-(3 -氯-苯基）-p密淀-2-基]-N-(4-三氣甲基-苯基）-胺 A) 1-(3 -氣-笨基）-3-二甲基月安_丙矯酉同(22) br · wide embodiment example 1 N- [4- (3-chloro-phenyl) -p dense lake-2-yl] -N- (4-trifluoromethyl-phenyl) -amine A) 1- (3 -Ga-benzyl) -3-dimethylmonthlyn

將50克3-苯氯乙酮及65毫升N，N-二甲基甲醯胺二甲縮 醛之混合物於約1 0 0度加熱約24小時再冷卻至室溫。將形 成的沉澱過濾、清洗並烘乾。得到結晶形式之40克1-(3-氯-苯基）-3·二甲基胺-丙烯酮。熔點72.8度。 B) 碳酸N-(4-三氟甲基-笨基胍A mixture of 50 g of 3-acetophenone and 65 ml of N, N-dimethylformamide dimethyl acetal was heated at about 100 degrees for about 24 hours and then cooled to room temperature. The formed precipitate was filtered, washed and dried. 40 g of 1- (3-chloro-phenyl) -3 · dimethylamine-propenone was obtained in crystalline form. Melting point is 72.8 degrees. B) N- (4-trifluoromethyl-benzylguanidine carbonate

將13.75毫升37%HC1水溶液逐滴加入17.5毫升4-三氟甲 基苯胺及2 8亳升的混合物中，將得到的混合物預先加熱至 約75度約20分鐘。將12.9克氰胺於13毫升水中的溶液逐滴 於7 5度加入得到的混合物中並於此溫度持續攪拌約4小時 。將得到的混合物冷卻至室溫並將9.26克Na2C03於43毫升 水中的溶液逐滴加入。將1 4 0毫升水加至得到的混合物中 並將得到的混合物攪拌隔夜。固體沉澱，過濾掉，清洗並 烘乾。得到結晶形式之14克碳酸N-(4-三氟甲基-苯基）-胍 。熔點1 2 5 · 3度。 C) N-f4-(3-氯-笨基嘧啶-2-基卜N-(4-三氟甲基-笨基胺 將1.5克1-(3 -氯-苯基）-3-二甲基胺-丙婦酬、1.7克碳酸 N-(4-三氟甲基·苯基）-胍及15毫升正丁醇之混合物於約 120度加熱約24小時，將得到的混合物冷卻至室溫而固體 沉澱。將沉澱過濾掉並自正丁醇再結晶。得到結晶形式之 -27- 200302728 (23) . . * I < 1·0克N-[4-(3-氯-苯基）-嘧啶·2-基]-N-(4·三氟甲基-苯基 )-胺。熔點201 _5度。 類似實例1中說明但利用適當起始材料（下式之化合物 ,.. - ，： ，其中RlEX、R2EX及R3EX為如下表1中所定義而R4EX為H) 得到具如下表1中所定義之熔點··： ,13.75 ml of a 37% HC1 aqueous solution was added dropwise to a mixture of 17.5 ml of 4-trifluoromethylaniline and 28 liters, and the resulting mixture was heated in advance to about 75 degrees for about 20 minutes. A solution of 12.9 g of cyanamide in 13 ml of water was added dropwise to the resulting mixture at 75 ° C and stirring was continued at this temperature for about 4 hours. The resulting mixture was cooled to room temperature and a solution of 9.26 g of Na2C03 in 43 ml of water was added dropwise. 140 ml of water was added to the obtained mixture, and the obtained mixture was stirred overnight. The solid precipitated, filtered off, washed and dried. 14 g of N- (4-trifluoromethyl-phenyl) -guanidine carbonate were obtained in crystalline form. Melting point 1 2 5 · 3 degrees. C) N-f4- (3-Chloro-benzylpyrimidin-2-yl) N- (4-trifluoromethyl-benzylamine) 1.5 g of 1- (3-chloro-phenyl) -3-dimethyl A mixture of succinylamine-propanone, 1.7 g of N- (4-trifluoromethyl · phenyl) -guanidine and 15 ml of n-butanol was heated at about 120 degrees for about 24 hours, and the resulting mixture was cooled to room temperature. The solid precipitated. The precipitate was filtered off and recrystallized from n-butanol. -27- 200302728 (23) was obtained in crystalline form. * I < 1.0 g of N- [4- (3-chloro-phenyl) -Pyrimidine · 2-yl] -N- (4 · trifluoromethyl-phenyl) -amine. Melting point 201-5 degrees. Similar to that described in Example 1 but using appropriate starting materials (compounds of the following formula, ..-, :, Where RlEX, R2EX, and R3EX are defined in the following Table 1 and R4EX is H) The melting points defined in the following Table 1 are obtained:

表1Table 1

實例 Riex &2EX R3EX 熔點（°c ) 2 cf3 cf3 F 168.0 3 Cl CF3 Cl 182.3 4 cf3 cf3 Cl 161.8 5 , cf3 H cf3 185.9 舍下式之化合物開始，Example Riex & 2EX R3EX Melting point (° c) 2 cf3 cf3 F 168.0 3 Cl CF3 Cl 182.3 4 cf3 cf3 Cl 161.8 5, cf3 H cf3 185.9 The compound of the following formula begins,

^4EX^ 4EX

-28- 200302728-28- 200302728

(24) 其中R4為氫，其為化合物N-[4-(3-氯-苯基）-嘧啶-2_基 ]_N-(4-三氟甲基-苯基）-胺，可得到下列實例6至68之化合 物，其中R4如該實例中定義。 實例6 式IIEX之化合物，其中R4EX為式-CO-CH3之基團 Ν·[4·(3 -氯-苯基）-口密淀_2_基]-N-(4-二氣甲基-苯基）-乙酿 胺(24) wherein R4 is hydrogen, which is the compound N- [4- (3-chloro-phenyl) -pyrimidin-2_yl] _N- (4-trifluoromethyl-phenyl) -amine, and the following can be obtained The compounds of Examples 6 to 68, wherein R4 is as defined in this example. Example 6 A compound of the formula IIEX, wherein R4EX is a group of the formula -CO-CH3, N · [4 · (3-chloro-phenyl) -kou dense lake_2_yl] -N- (4-difluoromethyl -Phenyl) -Ethylamine

將1.6克式IIEX之化合物（其中R4為氫）及3 00毫克4-二甲 基胺喊淀於3 0毫升無水峨淀之溶液以醋酸Sf處理並於7 0 度攪拌。由得到的混合物將溶劑蒸發掉，將二***加入並 將得到的沉澱過濾去除。將得到的濾液濃縮並將得到的濃 縮液經過矽膠中壓層析。由甲苯及戊烷混合物中得到 N-[4-(3-氯-苯基）-嘧啶-2-基]-N-(4-三氟甲基-苯基）-乙醯 胺於固體（結晶）粉末形式。熔點128.6- 129.6度。A solution of 1.6 g of a compound of formula IIEX (wherein R4 is hydrogen) and 300 mg of 4-dimethylamine in 30 ml of anhydrous Edo was treated with Sf acetate and stirred at 70 degrees. The solvent was evaporated from the resulting mixture, diethyl ether was added and the resulting precipitate was removed by filtration. The obtained filtrate was concentrated and the obtained concentrated liquid was subjected to silica gel medium pressure chromatography. N- [4- (3-chloro-phenyl) -pyrimidin-2-yl] -N- (4-trifluoromethyl-phenyl) -acetamidamine was obtained from a mixture of toluene and pentane in a solid (crystalline ) Powder form. Melting point is 128.6- 129.6 degrees.

類似實例6中說明但利用適當起始材料（式IIEX之化合 物，其中R4EX為如下表2中所定義）得到如下表2中所定義 之1H-NMR或熔點數據： -29- 200302728 (25)Similar to that illustrated in Example 6 but using appropriate starting materials (compounds of formula IIEX, where R4EX is defined in Table 2 below) to obtain 1H-NMR or melting point data as defined in Table 2 below: -29- 200302728 (25)

表2 實例 R4EX 熔點Ph-nmr 7 -CO-CH2-CH3 l 121*1° 8 -co-ch(ch3)2 , 122·122.8° 9 -CO-C6H5 ，130‘Γ 10 -CO-CH2-CH(CH3)2 109-110° 11 -CO-CO-CgHs 144.9° 12 -co-c(ch3)3 103.9-104.7° 13 -CO—<^〉 136.8° 14 'c〇O〇 * . * · · 158.8° 15 -CO-CO-0-CH2-CH3 133·70 ν 16 -C0-CH2"0~C0-CH3 150.8° 17 -CO-CO-0-CH3 Μ41.3。 18 -CO—<] 94.5-95.8° *·* ,： * ·. .. 19 -co-ch2-o-ch3 ν 124.6。 20 0 錢 - 'H-NMR (de-DMSO, 400 MHz, RT): 8.96(d, J=5.3,1H); 8.15(d; J=5.3,1H)· 7.95(d, J=8.3,2H), 7.70(t,J= 7.8,1 H), 7·60 (d, J=8.2,2H), 5·97 (q, J=6.7,1H), 2.06(s,3H), 1.69(d, J=6.7,3H) 實例2 1 *> 式ΙΙΕΧ之化合物，其中R4EX為下式之基團Table 2 Example R4EX Melting point Ph-nmr 7 -CO-CH2-CH3 l 121 * 1 ° 8 -co-ch (ch3) 2, 122 · 122.8 ° 9 -CO-C6H5, 130'Γ 10 -CO-CH2-CH (CH3) 2 109-110 ° 11 -CO-CO-CgHs 144.9 ° 12 -co-c (ch3) 3 103.9-104.7 ° 13 -CO— < ^〉 136.8 ° 14 'c〇O〇 *. * · 158.8 ° 15 -CO-CO-0-CH2-CH3 133 · 70 ν 16 -C0-CH2 " 0 ~ C0-CH3 150.8 ° 17 -CO-CO-0-CH3 Μ41.3. 18 -CO— <] 94.5-95.8 ° * · *,: * ·. .. 19 -co-ch2-o-ch3 ν 124.6. 2 0 0-'H-NMR (de-DMSO, 400 MHz, RT): 8.96 (d, J = 5.3,1H); 8.15 (d; J = 5.3,1H) · 7.95 (d, J = 8.3,2H ), 7.70 (t, J = 7.8,1 H), 7.60 (d, J = 8.2,2H), 5.97 (q, J = 6.7,1H), 2.06 (s, 3H), 1.69 (d , J = 6.7, 3H) Example 2 1 * > Compound of the formula ΙΙΕχ, where R4EX is a group of the formula

-30- 200302728-30- 200302728

(26) [4-(3-氯-苯基）-嘧啶-2-基]-(4-三孰甲基-苯基）-胺基甲酸 3-((S)_2-三級丁氧化羰胺基-丙醯胺）-丙基酯以游離鹼之 形式及以鹽酸鹽形式 將0.5克式IIEXi化合物（其中R4為氫）於30亳升無水氯 苯之溶液以〇 · 7 6毫升2 0 %光氣於甲苯溶液處理。將得到的 混合物於1 3 0 °C揽拌，將得到的澄清溶液冷卻至1 0 0 °C，將 另外的0 · 7 6毫升2 0 %光氣於甲苯溶液加入。將得到的混合 物於1 3 0 °C攪:摔，冷卻至1 0 0 °C ’並以氬氣處理以便去除多 餘光氣。將144微升[(S)-l_(3·經基-丙基氨基甲酸）乙基]_ 胺基甲酸三級丁基酯及1 3 〇微升吡啶於5毫升氯苯之溶液 知入得到的混合物中，將得到的混合物於1 3 0 °C攪拌’冷 啣至室溫。將得到的混合物以1 N鹽酸溶液、飽和NaHC〇3 溶液及鹽水清洗並濃縮。將得到的濃縮液經過矽膠急速層 折。得到[4-(3-氯-苯基）-嘧啶_2-基]-(4-三氟甲基·苯基）-膝基甲酸3 - (( S ) - 2 -三級丁氧化黢胺基-丙醯胺丙基酯以 淹之形式。1H-NMR(CDCh，400 MHz，RT)(5 :8.77 (d; 1H)， 7·94 (s; 1H)，7.83 (d; 1H)，7.69 (d; 1H)，7·51 (d; 1H)， 7·5〇·7·38 (m; 4H)，4.35 (t; 2H)5 3.16 (m; 2H)，1.84 (m; 2H)，1.43 (s; 9H)。 將276毫克[4-(3-氯-苯基）_嘧啶-2-基]-(4-三氟甲基-苯 基）·胺基甲酸3-((S)-2_三級丁氧化羰胺基-丙醯胺）-丙基 西匕、人 —曰义三氟乙酸之溶液攪拌约2小時。由得到的混合物將溶 劑蒸發掉並將得到的蒸發殘餘物溶解於***中。將得到的 匕b物以HC1於***中處理。以鹽酸鹽形式之[4-(3-氯_苯 200302728(26) [4- (3-Chloro-phenyl) -pyrimidin-2-yl]-(4-trismethyl-phenyl) -aminocarboxylic acid 3-((S) _2-tertiary butoxycarbonyl Amine-Propanamine) -propyl ester in the form of a free base and in the form of a hydrochloride salt of 0.5 g of a compound of formula IIEXi (where R4 is hydrogen) in 30 liters of anhydrous chlorobenzene in 0.76 ml 2 0% phosgene in toluene solution. The resulting mixture was stirred at 130 ° C, the resulting clear solution was cooled to 100 ° C, and another 0.76 ml of 20% phosgene was added to the toluene solution. The resulting mixture was stirred at 130 ° C: dropped, cooled to 100 ° C 'and treated with argon to remove excess phosgene. 144 μl of a solution of [(S) -l_ (3-Cyclo-propylcarbamic acid) ethyl] -tributylaminocarbamate and 130 μl of pyridine in 5 ml of chlorobenzene were obtained. In the mixture, the obtained mixture was stirred at 130 ° C and cooled to room temperature. The resulting mixture was washed with a 1 N hydrochloric acid solution, a saturated NaHC03 solution, and brine, and concentrated. The obtained concentrated liquid was rapidly folded through silicone. [4- (3-Chloro-phenyl) -pyrimidin_2-yl]-(4-trifluoromethyl · phenyl) -kanoic acid 3-((S)-2 -tertiary butylamine oxide -Propylamidopropyl ester in the form of 1H-NMR (CDCh, 400 MHz, RT) (5: 8.77 (d; 1H), 7.94 (s; 1H), 7.83 (d; 1H), 7.69 (d; 1H), 7.51 (d; 1H), 7.50 (7; 38 (m; 4H), 4.35 (t; 2H) 5 3.16 (m; 2H), 1.84 (m; 2H) , 1.43 (s; 9H). 276 mg of [4- (3-chloro-phenyl) _pyrimidin-2-yl]-(4-trifluoromethyl-phenyl) · aminocarboxylic acid 3-((S ) -2_ Tertiary butoxycarbonylamino-propylammonium amine) -propyl dagger, human-Yiyi trifluoroacetic acid solution was stirred for about 2 hours. The solvent was evaporated from the resulting mixture and the resulting evaporation residue The product was dissolved in ether. The obtained product was treated with HC1 in ether. [4- (3-chloro_benzene200302728)

(27) l^W(27) l ^ W

基）-p密症-2 -基]-(4-二氣甲基·苯基）-胺基甲酸3-((S)-2· 三級丁氧化羰胺基-丙醯胺）-丙基酯沉澱，將其過濾、清 洗及烘乾。熔點：54.6-54.8°C 類似實例2 1中說明之方法，但利用適當起始材料（式 IIEX之化合物，其中R 4EX 為如下表3中所定義）得到如表3 中所定義之1H-NMR或熔點數據： 表3 實例、 R4EX 熔點"h-nmr 22 0 65.7-72.9° 23 . 1 Y°^ch3 0 192.5-194.2° ' * - 24 八/0H 0 ^ . · » r 1 11 1 1 191.9-193.7° 25 ΗΓΛ 丫 0 ♦126·8-130·8° 26 0 161-162.8° 27 yn2 ， ^^^COOH 138.1-143.2° 200302728 28 , i . . 〇 人^CH' 0 nh2 V. ^ 1H-NMR (de-DMSOf 400 MHz, RT) δ: 8.86(d;1H), 8.44(bd;3H), 8.15(m;1H)f 8.10(m;1H)f 8.06(d;1H), 7.76/7.51 (AB-system;4H), 7.64(m;1H)f 7.57(t；1H), 4.62-4.36(m;3H)f 4.32-4.28(m;1H), 4.02-3,98(m;1H), 1.26(d;3H) 29a 0 丫^Y^SfCH3 0 nh2 鏵 · t ' · 133-136.3° . . . .· · . · •、 ( * 1 4 1 1 ' 29b 如實例29a 185.6-187.1° 30 0 OH o nh2 —’， · * ， 91.9-95° < ·、,、 · 31 .Α〇^^〇Λ^νη2 1H-NMR (de-DMSO): 8.85 (d; 1H)f 8.23 (br; 2H)f 8.14 (m; 1H), 8.10 (m; 1H), 8.06 (d; 1H), 7J6 (d; 2H)f 7.64 7.59 (t; 1H), 7.49 (d; 2H), 4.28 (m; 2H)f 4.12 (m; 2H), 4.07 (q, 1H), 1.93 (m；2H)f 1.34 (d; 3H) 於表3中，熔點或1H-NMR數據為實例22至28、29a及30 以鹽酸鹽形式之化合物數據，對於實例29b以苯橫酸 (b e s y 1 a t e)鹽形式及對於實例3 1以三氣乙練形式。 * ， ， 〆 . 實例3 2:a 式IIex之化合物，其中R4EX為下式之基團) -P-dense-2 -yl]-(4-difluoromethyl · phenyl) -carbamic acid 3-((S) -2 · tertiary butoxycarbonylamino-propylammonium) -propyl The base ester precipitates and is filtered, washed and dried. Melting point: 54.6-54.8 ° C Similar to the method described in Example 21, but using appropriate starting materials (compounds of formula IIEX, where R 4EX is as defined in Table 3 below) gives 1H-NMR as defined in Table 3 Or melting point data: Table 3 Examples, R4EX melting point " h-nmr 22 0 65.7-72.9 ° 23. 1 Y ° ^ ch3 0 192.5-194.2 ° '*-24 8 / 0H 0 ^. · »R 1 11 1 1 191.9-193.7 ° 25 ΗΓΛ YA0 ♦ 126 · 8-130 · 8 ° 26 0 161-162.8 ° 27 yn2, ^^ COOH 138.1-143.2 ° 200302728 28, i.. 〇 人 ^ CH '0 nh2 V. ^ 1H-NMR (de-DMSOf 400 MHz, RT) δ: 8.86 (d; 1H), 8.44 (bd; 3H), 8.15 (m; 1H) f 8.10 (m; 1H) f 8.06 (d; 1H), 7.76 /7.51 (AB-system; 4H), 7.64 (m; 1H) f 7.57 (t; 1H), 4.62-4.36 (m; 3H) f 4.32-4.28 (m; 1H), 4.02-3,98 (m; 1H), 1.26 (d; 3H) 29a 0 ^^^^ SfCH3 0 nh2 t · t '· 133-136.3 °..... · ·, (* 1 4 1 1' 29b as example 29a 185.6- 187.1 ° 30 0 OH o nh2 — ', · *, 91.9-95 ° < · ,,, · 31 .Α〇 ^^ 〇Λ ^ νη2 1H-NMR (de-DMSO): 8.85 (d; 1H) f 8.23 (br; 2H) f 8.14 (m; 1H), 8.10 (m; 1H), 8.06 (d; 1H), 7J6 (d; 2H) f 7.64 7.59 (t; 1H), 7.49 (d; 2H), 4.28 (m; 2H) f 4.12 (m; 2H), 4.07 (q, 1H), 1.93 (m; 2H) f 1.34 (d; 3H) at In Table 3, the melting point or 1H-NMR data are the data of the compounds in Examples 22 to 28, 29a, and 30 in the form of the hydrochloride salt, for Example 29b in the form of besy 1 ate salt, and for Example 31 in the form of triple gas The second form. *,, 〆. Example 3 2: a compound of formula IIex, where R4EX is a group of the formula

[4-(3-氯-苯基）-癌喊-2 -基]-(4-三氟甲基-苯基）-胺基曱 酸2-[(2-羥乙基）-甲基-胺基;1-乙基酯以鹽酸鹽形式 :; ； 將0.5克式ΙΙΕχ之化合物（其中R4為氫）於3〇毫升無水氯 苯之溶液以0.76毫升20%光氣於甲苯溶液處理。將得到的 混合物於130°C攪拌，將得到的澄清I溶液冷卻至l〇〇°C，將 -33 200302728 (29)[4- (3-Chloro-phenyl) -cancer-2 -yl]-(4-trifluoromethyl-phenyl) -aminophosphonic acid 2-[(2-hydroxyethyl) -methyl- Amine; 1-ethyl ester in the form of the hydrochloride: ;; a solution of 0.5 g of a compound of formula IIEX (where R4 is hydrogen) in 30 ml of anhydrous chlorobenzene was treated with 0.76 ml of 20% phosgene in toluene solution. The resulting mixture was stirred at 130 ° C, the resulting clear I solution was cooled to 100 ° C, and -33 200302728 (29)

另外的0 · 7 6毫升2 0 %光氣於甲苯溶液加入。將得到的混合 物於130°C攪拌，冷卻至10(TC，並以氬氣處理以便去除多 餘光氣。將得到的混合物淤室溫，.以0.675毫升2-[(2-羥乙基 )-甲基-胺基]•乙醇於5毫升氯苯之溶液處理並於1 3 0 °C攪: 拌，冷卻至室溫並真空濃縮。將得到的濃*縮殘餘物溶解於 乙酸乙酯中並以水溶液、，飽和NaHC03溶液及鹽水清洗。 將得到的有機層以醋酸處理，將得到的混合物於真空中濃 鑰並將得到的濃縮液經過層析。將得到的[4-(3-氯-苯基）-嘧啶_2_基]-(4-三氟甲基-苯基）-胺基甲酸2-[(2-羥乙基）-甲基-胺基]-乙基酯以鉍酸鹽形式以HC1於***中處理。以 鹽酸鹽形式之[4-(3-氯-苯基）-嘧啶-2-基]-(4-三氟曱基-苯 基）-胺基甲酸2-[(2-#垔乙基）-曱基·胺基]-乙基醋沉殿（結 晶），將其過濾、清洗及烘乾。熔點：1 4 5.9 - 1 4 7 · 7 °C。 類似實例3 2 a中說明之方法，但利用適當起始材料（式 Hex之化合物’其中R4ex為如下表4中所定義）得到如表4An additional 0.76 ml of 20% phosgene was added to the toluene solution. The resulting mixture was stirred at 130 ° C., cooled to 10 ° C., and treated with argon to remove excess phosgene. The resulting mixture was sludge at room temperature, and 0.675 ml of 2-[(2-hydroxyethyl)- Methyl-amino] • ethanol was treated with a solution of 5 ml of chlorobenzene and stirred at 130 ° C: stirred, cooled to room temperature and concentrated in vacuo. The resulting concentrated and condensed residue was dissolved in ethyl acetate and It was washed with aqueous solution, saturated NaHC03 solution and brine. The obtained organic layer was treated with acetic acid, the obtained mixture was concentrated in vacuo, and the obtained concentrated solution was subjected to chromatography. The obtained [4- (3-chloro- Phenyl) -pyrimidin-2-yl]-(4-trifluoromethyl-phenyl) -aminocarboxylic acid 2-[(2-hydroxyethyl) -methyl-amino] -ethyl ester with bismuth acid The salt form is treated with HC1 in ether. [4- (3-chloro-phenyl) -pyrimidin-2-yl]-(4-trifluorofluorenyl-phenyl) -aminocarboxylic acid 2 as the hydrochloride salt -[(2- # 垔 ethyl) -fluorenyl · amino] -ethyl vinegar (crystal), filter, wash and dry. Melting point: 1 4 5.9-1 4 7 · 7 ° C. Similar to the method described in Example 3 2a, but using appropriate starting materials (combination of formula Hex 'Wherein R4ex is as defined below in Table 4) Table 4 to give

中所定義之1H-NMR或熔點數據： 表4 '實例 R4EX /'H-NIVIR 32b 如實例32a1' ' ., 119.5° ,32c 如實例32a : 190.2-190.7° 32d ，如實例32a… V ： 66.5-72.2° 32θ 如實例32a 134.1-135.5° * * 32f 如實例32a 一 130.4-132.5° 33 -CO-0-CH2-CH3 ，68.3-69.2° 34 Ύ。〜Γι Η 0 1 151.3-154.3° -34- (30)200302728 35 361H-NMR or melting point data defined in: Table 4 'Example R4EX /' H-NIVIR 32b as example 32a1 ''., 119.5 °, 32c as example 32a: 190.2-190.7 ° 32d, as example 32a ... V: 66.5 -72.2 ° 32θ as in Example 32a 134.1-135.5 ° * * 32f as in Example 32a-130.4-132.5 ° 33 -CO-0-CH2-CH3, 68.3-69.2 ° 34 Ύ. ~ Γι Η 0 1 151.3-154.3 ° -34- (30) 200302728 35 36

<ninwrMa!fiaMaaiBaat^ajfffipsaByt»BgTOrffla^rfH 171.2-174.3° 128.9-129.1° 37 丫 Ή-NMR (DMSO-d6, 400 MHz, RT) δ: 8.85(d;1H),.8.15(m;1H), 8.10(m;1H), 8.04(d;1H), 7.75/7.48 (AB,systen1\4H); 7.63(m; 1H), 7.57(t; 1H), 4.46(t; 1H), ^ 4.25(t;2H), 3.34(dt;2H), 1.69(d;2H) 38< ninwrMa! fiaMaaiBaat ^ ajfffipsaByt »BgTOrffla ^ rfH 171.2-174.3 ° 128.9-129.1 ° 37 Yamma-NMR (DMSO-d6, 400 MHz, RT) δ: 8.85 (d; 1H), .8.15 (m; 1H) , 8.10 (m; 1H), 8.04 (d; 1H), 7.75 / 7.48 (AB, systen1 \ 4H); 7.63 (m; 1H), 7.57 (t; 1H), 4.46 (t; 1H), ^ 4.25 ( t; 2H), 3.34 (dt; 2H), 1.69 (d; 2H) 38

0、 O0, O

/CH3 I \ CK 152J-156.20 39/ CH3 I \ CK 152J-156.20 39

40 154.9-16Z8° 1H-NMR (d6-DMSO, 400 MHz, RT) δ: 8.86(d;1H), 8.11-8.05(m;3H), 7-79(d; 2H); 7·64 -7.57(m;4H)，4.62(bs;2H), 3.60-3.40(m;8H), 3.40-3.25(m;2H), 2.76 (s； 3H) _ _ 於表4中，實例i 離驗形式化合物之赵 G之溶點或1™數據為以游 或1H-NMR數據為f瞄據，實例34、35、36、38及39之熔點 、 、、 爆為以鹽酸鹽形式化合物之數據，實例32b 至32f(熔點為下列鹽類之數據：32b)甲磺酸（mesylate) 鹽’ 32c)硫酸鹽，32c)酒石酸鹽，32e)對甲苯磺酸鹽及32f) 苯磺酸（besylate)鹽。 實例4 1 丨 式IIEX之化合物，其中R4EX為-CH3 [,4_(3-氯-苯基）_嘧啶-2-基]曱基- (4-三氟甲基-苯基）_胺 將1.60毫克式Πεχ之化合物（其中R4為氫）於4毫升:無水二 甲基甲醯胺之溶液以N aH處理，將得到的混合物於1 〇 〇 °c 攪拌，冷卻至室溫並以5 7微升甲基碘處理。將得到的混合 -35- 200302728 _ (31) 物於室溫攪拌隔夜。自得到的混合物將沉澱過濾掉，將得 到的濾液真空濃縮。將得到的濃縮殘餘物經過矽膠急速層 析。得到的[4-(3 -氯·苯基）-p密淀-2-基]-甲基- (4-三氟甲基· 苯基）-胺自正戊烷以固體之形式沉澱，將其過濾及烘乾。 由1H-NMR資料確認結構。 · 類似實例4 1中說明之方法，但利用適當起始，材料，將式 IIEX之化合物（其中R4EX為CH3)製備。 實例 42 iH-NMRJ.SSd J = 5.2 Hz，lH); 7.49(d，lH); 3.59(s，3H) 實例43 R4EX 為-co-n(ch3)2 1 將0_5克Ν-[4-(3·氯-苯基）-嘧啶-2_基]·Ν-(4-三氟甲基· 苯基）-胺、86毫克NaH、0.4毫升Ν，Ν-二甲基胺基甲醯氯於 5毫升Ν，Ν-二甲基甲醯胺之混合物於80 °C加熱4小時。將 溶劑蒸發掉並將乙酸乙酯加入得到的殘餘物中。清洗及乾 燥後，將得到的濃縮物經過矽膠層析並得到產物。熔點為 143〇C。 實例 44 — —.. 一— ... ____________,-------40 154.9-16Z8 ° 1H-NMR (d6-DMSO, 400 MHz, RT) δ: 8.86 (d; 1H), 8.11-8.05 (m; 3H), 7-79 (d; 2H); 7.64 -7.57 (m; 4H), 4.62 (bs; 2H), 3.60-3.40 (m; 8H), 3.40-3.25 (m; 2H), 2.76 (s; 3H) _ _ In Table 4, Example i Compound in isolated form Zhao G ’s melting point or 1 ™ data is based on fugitive or 1H-NMR data. The melting points of Example 34, 35, 36, 38, and 39 are the data of compounds in the form of hydrochloride. Examples 32b to 32f (melting point data for the following salts: 32b) mesylate salt '32c) sulfate, 32c) tartrate, 32e) p-toluenesulfonate and 32f) besylate salt. Example 4 1 Compound of the formula IIEX, wherein R4EX is -CH3 [, 4- (3-chloro-phenyl) _pyrimidin-2-yl] fluorenyl- (4-trifluoromethyl-phenyl) _amine will be 1.60 Mg of a compound of formula Πεχ (wherein R4 is hydrogen) in 4 ml: a solution of anhydrous dimethylformamide in NaH, and the resulting mixture was stirred at 1000 ° C, cooled to room temperature and treated with 5 7 micro L methyl iodide treatment. The resulting mixture -35- 200302728 _ (31) was stirred at room temperature overnight. The precipitate was filtered off from the resulting mixture, and the resulting filtrate was concentrated in vacuo. The resulting concentrated residue was subjected to rapid silica gel layer analysis. The obtained [4- (3-chloro · phenyl) -p dense lake-2-yl] -methyl- (4-trifluoromethyl · phenyl) -amine was precipitated from n-pentane as a solid, and It is filtered and dried. The structure was confirmed from the 1H-NMR data. · A method similar to that described in Example 41, but using appropriate starting materials, was prepared from a compound of formula IIEX (wherein R4EX is CH3). Example 42 iH-NMRJ.SSd J = 5.2 Hz, lH); 7.49 (d, lH); 3.59 (s, 3H) Example 43 R4EX is -co-n (ch3) 2 1 0-5 g of N- [4- ( 3 · Chloro-phenyl) -pyrimidin-2-yl] · N- (4-trifluoromethyl · phenyl) -amine, 86 mg NaH, 0.4 ml N, N-dimethylaminoformyl chloride 5 ml of a mixture of Ν, Ν-dimethylformamide was heated at 80 ° C for 4 hours. The solvent was evaporated off and ethyl acetate was added to the obtained residue. After washing and drying, the obtained concentrate was subjected to silica gel chromatography to obtain a product. Melting point was 143 ° C. Example 44 — — .. One — ... ____________, -------

將1克N-[4-(3-氯-苯基）-嘧啶-2-基]-N-(4_三氟甲基-苯 基）-胺、1.9 8毫升氯化glutaric acid單甲基酯、1.1毫升吡 啶及1 0毫克二甲基胺吡啶於2 5毫升甲苯之混合物加熱。將 混合物以乙酸乙酯稀釋，以冷〇 · 〇 1 N H C1水溶液、碳酸氫 -36- (32) 2003027281 g of N- [4- (3-chloro-phenyl) -pyrimidin-2-yl] -N- (4-trifluoromethyl-phenyl) -amine, 1.98 ml of glutaric acid monomethyl chloride A mixture of the ester, 1.1 ml of pyridine and 10 mg of dimethylaminopyridine was heated in 25 ml of toluene. The mixture was diluted with ethyl acetate and cooled with a cold aqueous solution of 1 N H C1, bicarbonate -36- (32) 200302728.

鹽水溶液及鹽水清洗。將有機相乾燥，i、、4 %床’將落劑蒸發，得到 產物。（d6-DMSO, 500 MHz，RT):8.83 Η t —c a J = 5.251H); 8.12-8.10 (m，1H); 8·10·8·07 (m，1H); 8.02 (d5 J = 5 9 〜1H)； 7.79 (d? J==8i55 2H); 7.65-7.62 (m，1H); 7.57 (t，J = 7· 3.53 (s; 3H); 2.84 (t，J = 7.3，2H); ^ iH); 7.47 (d5 J = 8.25 2H); 2·38 (t，，J二7.5，2H); 1.89 (quintett, J = 7.3? 2H) 類似實例44中說明，但利用適當起始材料（式i之化合物 ’其中Lex為如下表5中所定義）得到如表$中所定義之 ^-NMWcU-DMSO, 500 MHz，RT，除非另外指明）或熔點 數據： ， 表5 實W R4EX 熔黑P^-Nmr 45 0 T 1 (d, J = 5.2,1H); 8.12-8.11 (m, 1H); 8.10 - 8.08 (m, 1H); 8.02 (d, J = 5.2, 1H); 7.78 (d, J = 8.5, 2H); 7.65 - 7.62 (m, 1H); 7.58 (t, J = 7.9, 1H); 7.45 (d, J = 8.3, 2H); 3.54 (s, 3H); 2.79 (tf J = 7.5, 2H); 2.29 (m, 2H); 1.68 - 1.62 (m, 2IH); 1.52 -1.48 (m, 2H) ; 46 〇 (400 MHz): 8.84 (d, J = 5.3, 1H); 8.13 -8.09 (m, 2H); 8.02 (d, J = 5.3, 1H); 7.80 (d, J = 8.4, 2H); 7.64 - 7.62 (m, 1H); 7.57 (t, J =7.8,1H); 7.46 (d, J = 8.2, 2H); 3.59 (s, 3H); 3.12 - 3.08 (m, 2H); 2.68 - 2.65 (m, 2H) 47 0γ^〇^γ0\ 0 8J7 (d, J = 5.5,1H); 8.08 - 8.07 (m, 2H); 7.96 (d, J = 5.2,1H); 7.83 (d, J = 8.5, 2H); 7.65 - 7.62 (m, 1H)； 7.57 (t, J = 8.1, 1H); 7.51 (d, J = 8.2, 2H)； 4.90 (s, 2H); 4.22 (s, 2H); 3.61 (s, 3H) 48 0 8.79 (d, J = 5.5,1H)； 8.11 - 8.10 (m, 1H); 8.09 - 8.08 (m, 1H)； 7.98 (d, J = 5.2, ^H); 7.81 (d, J - 8.2, 2H)； 7.65 - 7.62 (m, 1H); 7.58 (t, J = 8.1, 1H)； 7.47 (d, J = 8.2, 2H); 4.72 (s, 2H), 3.56 - 3.54 (m, 2H); 3.34 - 3.32 (m,2ri): 3.14 (s, 3H)_ -37- (33)200302728Rinse with saline solution and brine. The organic phase was dried and the eluent was evaporated on a 4% bed 'to give the product. (D6-DMSO, 500 MHz, RT): 8.83 Η t —ca J = 5.251H); 8.12-8.10 (m, 1H); 8.10 · 8 · 07 (m, 1H); 8.02 (d5 J = 5 9 ~ 1H); 7.79 (d? J == 8i55 2H); 7.65-7.62 (m, 1H); 7.57 (t, J = 7.3.53 (s; 3H); 2.84 (t, J = 7.3, 2H) ^ iH); 7.47 (d5 J = 8.25 2H); 2.38 (t, J = 7.5, 2H); 1.89 (quintett, J = 7.3? 2H) similar to that described in Example 44 but using appropriate starting materials (Compound of formula i where Lex is as defined in Table 5 below) gives ^ -NMWcU-DMSO, 500 MHz, RT as defined in Table $ or melting point data:, Table 5 Black P ^ -Nmr 45 0 T 1 (d, J = 5.2, 1H); 8.12-8.11 (m, 1H); 8.10-8.08 (m, 1H); 8.02 (d, J = 5.2, 1H); 7.78 ( d, J = 8.5, 2H); 7.65-7.62 (m, 1H); 7.58 (t, J = 7.9, 1H); 7.45 (d, J = 8.3, 2H); 3.54 (s, 3H); 2.79 (tf J = 7.5, 2H); 2.29 (m, 2H); 1.68-1.62 (m, 2IH); 1.52-1.48 (m, 2H); 46 〇 (400 MHz): 8.84 (d, J = 5.3, 1H); 8.13 -8.09 (m, 2H); 8.02 (d, J = 5.3, 1H); 7.80 (d, J = 8.4, 2H); 7.64-7.62 (m, 1H); 7.57 (t, J = 7.8,1H) ; 7.46 (d, J = 8.2, 2 H); 3.59 (s, 3H); 3.12-3.08 (m, 2H); 2.68-2.65 (m, 2H) 47 0γ ^ 〇 ^ γ0 \ 0 8J7 (d, J = 5.5, 1H); 8.08-8.07 ( m, 2H); 7.96 (d, J = 5.2, 1H); 7.83 (d, J = 8.5, 2H); 7.65-7.62 (m, 1H); 7.57 (t, J = 8.1, 1H); 7.51 (d , J = 8.2, 2H); 4.90 (s, 2H); 4.22 (s, 2H); 3.61 (s, 3H) 48 0 8.79 (d, J = 5.5, 1H); 8.11-8.10 (m, 1H); 8.09-8.08 (m, 1H); 7.98 (d, J = 5.2, ^ H); 7.81 (d, J-8.2, 2H); 7.65-7.62 (m, 1H); 7.58 (t, J = 8.1, 1H ); 7.47 (d, J = 8.2, 2H); 4.72 (s, 2H), 3.56-3.54 (m, 2H); 3.34-3.32 (m, 2ri): 3.14 (s, 3H) _ -37- (33 200302728

實例49aExample 49a

Ιεχ為 將〇·01 NNa〇H7jC溶液逐滴加入4.5克N-[4-(3-氯-苯基）-=淀-2-基]養（4-三氟甲基苯基卜胺於四氣咬喃及水之混 1物的命液中。將形成的沉澱過濾掉並將溶劑蒸乾。將得 、二發殘田物過濾並將得到的濾液以〇· 1 N HC1酸化至 PH 以乙酸乙酯萃取。將有機相清洗及乾燥，將溶劑除 —而知到固體。自〔氯甲烷及戊烷混合物結晶產生產物。 、七占 138.6 C 〇 H_NMR : (d6-DMSO, 500 MHz，RT): 12.01 1 ’ ⑸),8.83 (d，J = 5'2，1H); 8.10 (m，ih); 8.09- 8.07 (m， )’ 8·〇1 (d，J = 5.4，1H); 7.78 (d，J = 8:7, 2H); 7.63-7.61 (m， H)’ 7.56 (t，J = 7.8，1H); 7.47 (d，J = 8.7, 2H); 2.84 (t，J = 7.5, 2H), 2.29 (t，J = 7.4，2H); 1.87 (quintett，J = 7.3，2H) 實例49b 將40毫克氫氧化鈣加入0.5克實例49a化合物’、u毫升四 氧味喃及5毫升水之混合物中。將得到的混合物搖動數分 鐘並於室溫中靜置。將分，離的晶體過濾並以冷異丙醇清洗 而得到實例49a化合物之鈣鹽。 'H-NMR : (d6-DMS05 400 MHz, RT): 8.83 (d? J-5.3)； 8.00 (d? J，5.3); 7.78 (d，J=8.5); 7.45 (d，J=8.3);. 2.78 (t5 J=7·”； 199 (t， J^7*3)； 1.8 (m) ， ， 類似實例49a中說明，但利用適當起始材料（式！之化合 物 其中R4 e X為如下表6中所定義）得到如表6中所定義之 -38- 200302728 (34) iH-NMRdDMSO，500 MHz，RT)或溶點·· 表6Ιεχ is the dropwise addition of a solution of 0.01 NNaOH7jC to 4.5 g of N- [4- (3-chloro-phenyl)-= yodo-2-yl] sulphate The gaseous acid and water are mixed in the solution of the liquid. The formed precipitate is filtered off and the solvent is evaporated to dryness. The obtained and secondary residues are filtered and the obtained filtrate is acidified with 0.1N HC1 to pH to Ethyl acetate extraction. The organic phase was washed and dried, and the solvent was removed—a solid was obtained. The product was produced by crystallization from a mixture of [chloromethane and pentane. ): 12.01 1 '⑸), 8.83 (d, J = 5'2, 1H); 8.10 (m, ih); 8.09- 8.07 (m,)' 8.〇1 (d, J = 5.4, 1H); 7.78 (d, J = 8: 7, 2H); 7.63-7.61 (m, H) '7.56 (t, J = 7.8, 1H); 7.47 (d, J = 8.7, 2H); 2.84 (t, J = 7.5, 2H), 2.29 (t, J = 7.4, 2H); 1.87 (quintett, J = 7.3, 2H) Example 49b 40 mg of calcium hydroxide was added to 0.5 g of the compound of Example 49a ', u ml of tetraoxan and 5 In a mixture of ml of water. The resulting mixture was shaken for several minutes and left to stand at room temperature. The separated and separated crystals were filtered and washed with cold isopropanol to obtain the calcium salt of the compound of Example 49a. 'H-NMR: (d6-DMS05 400 MHz, RT): 8.83 (d? J-5.3); 8.00 (d? J, 5.3); 7.78 (d, J = 8.5); 7.45 (d, J = 8.3) ;. 2.78 (t5 J = 7 · ”; 199 (t, J ^ 7 * 3); 1.8 (m),, similar to that described in Example 49a, but using appropriate starting materials (compounds of formula! Where R4 e X is (As defined in Table 6 below) -38- 200302728 (34) iH-NMRdDMSO, 500 MHz, RT) or melting point as defined in Table 6

實例 R4EX 熔點n^NMR · , . 50 0 11.98 (br, 1H); 8.83 (d, J = 5.3, 1H); 8.12-8.11 (mf 1H); 8.10-8.08 (m, 1H); 8.01 (d, J = 5.3,1H); 7.78 (d, J = 8.3, 2H); 7.65 - 7.62 (m, 1H); 7.57 (t, J = 7.8,1H); 7.45 (d, J = 8.3, 2H)； 2.79 (t, J =7.5, 2H)； 2.19 (tf j = 7.3, 2H)； 1.69 -1.63 (m, 2H); 1.56-1.50 (mf 2H) 51 8.82 (d, J = 5.5, 1H)； 8.15 (d, J = 7.3, 1H); 8.12 - 8.08 (mf 2H); 8.00 (d, J^= 5.2, 1H); 7.78 (d, J = 8.2, 2H); 7.65 -7.62 (m, 1H); 7.57 (t, J = 7.8,1H); 7.46 (d, J = 8.2, 2H); 4.16 (quintet^ J = 7.2,、 1H); 3.05 - 2.95 (m, 2H); 2；58 - 2.52 (m, 2H);1.22 (d,J = 7.3, 3H) 52 0 °γ^γ^〇Η 12,40 (br., 1H); 8.83 (d, J = 5.5,1H); 8.11 - 8.08 (m, 2H); 8.05 (d, J = 7.3, 1H); 8.02 (d, J = 5.5, 1H); 7.78 (d, J = 8.5, 2H); 7.64 - 7,62 (m, 1H); 7.57 (t, J =7.8, 1H); 7.47 (d, J = 8.2, 2H); 4.16 -4.09 (m, 1H); 2.80 - 2.76 (m, 2H); 2.16 (t, J = 7.3, 2H); 1.89 - 1.81 (m, 2H); 1.17 (d,J = 7.3, 3H) 53 • 〇 . 八。八Z 丫^。H ο 1 • . · 8.78 (d, J = 5.2, 1H); 8.09 - 8.06 (m, 2H); 7.97 (d, J = 5.2, 1H); 7.95 (d, J = 7.5,1H); 7.83 (d, J = 8.5, 2H); 7.64 -7.62 (m, 1H); 7.57 (t, J = 7.8,1H); 7.52 (d, J = 8.5, 2H); 4.90 (s, 2H)； 4.26 -4.18 (m, 1H); 4.01 (s, 2H); 1.24 (d, J = 7.0, 3H)Example R4EX Melting point n ^ NMR ·,. 50 0 11.98 (br, 1H); 8.83 (d, J = 5.3, 1H); 8.12-8.11 (mf 1H); 8.10-8.08 (m, 1H); 8.01 (d, J = 5.3, 1H); 7.78 (d, J = 8.3, 2H); 7.65-7.62 (m, 1H); 7.57 (t, J = 7.8, 1H); 7.45 (d, J = 8.3, 2H); 2.79 (t, J = 7.5, 2H); 2.19 (tf j = 7.3, 2H); 1.69 -1.63 (m, 2H); 1.56-1.50 (mf 2H) 51 8.82 (d, J = 5.5, 1H); 8.15 ( d, J = 7.3, 1H); 8.12-8.08 (mf 2H); 8.00 (d, J ^ = 5.2, 1H); 7.78 (d, J = 8.2, 2H); 7.65 -7.62 (m, 1H); 7.57 (t, J = 7.8,1H); 7.46 (d, J = 8.2, 2H); 4.16 (quintet ^ J = 7.2 ,, 1H); 3.05-2.95 (m, 2H); 2; 58-2.52 (m, 2H); 1.22 (d, J = 7.3, 3H) 52 0 ° γ ^ γ ^ 〇Η 12,40 (br., 1H); 8.83 (d, J = 5.5,1H); 8.11-8.08 (m, 2H ); 8.05 (d, J = 7.3, 1H); 8.02 (d, J = 5.5, 1H); 7.78 (d, J = 8.5, 2H); 7.64-7,62 (m, 1H); 7.57 (t, J = 7.8, 1H); 7.47 (d, J = 8.2, 2H); 4.16 -4.09 (m, 1H); 2.80-2.76 (m, 2H); 2.16 (t, J = 7.3, 2H); 1.89-1.81 (m, 2H); 1.17 (d, J = 7.3, 3H) 53 • 〇.八 Z 呀 ^. H ο 1 •. · 8.78 (d, J = 5.2, 1H); 8.09-8.06 (m, 2H); 7.97 (d, J = 5.2, 1H); 7.95 (d, J = 7.5, 1H); 7.83 ( d, J = 8.5, 2H); 7.64 -7.62 (m, 1H); 7.57 (t, J = 7.8,1H); 7.52 (d, J = 8.5, 2H); 4.90 (s, 2H); 4.26 -4.18 (m, 1H); 4.01 (s, 2H); 1.24 (d, J = 7.0, 3H)

-39- 200302728 (35) 將1.97毫升二異丙基乙基胺逐滴加入2克N-[4-(3-氯-苯 基）·嘧啶-2-基]-N-(4-三氟甲基-苯基）-胺、1.21毫升琥珀 醯氯及1 〇毫克二甲基胺吡啶於C Η 2 C12中之混合物中。將混 合物於室溫攪拌，冷卻並將2克L-丙胺酸甲基酯鹽酸鹽加 入。將3.4毫升二異丙基乙基胺逐滴加入並再攪拌。將得 到的混合物以乙酸乙酯稀釋、清洗及乾燥，將溶劑蒸發並 於結晶後得到產物（熔點：170.9 °C )。-39- 200302728 (35) 1.97 ml of diisopropylethylamine was added dropwise to 2 g of N- [4- (3-chloro-phenyl) · pyrimidin-2-yl] -N- (4-trifluoro Methyl-phenyl) -amine, 1.21 ml of succinic chloride and 10 mg of dimethylamine pyridine in a mixture of CC 2 C12. The mixture was stirred at room temperature, cooled and 2 g of L-alanine methyl ester hydrochloride was added. 3.4 ml of diisopropylethylamine was added dropwise and stirred again. The resulting mixture was diluted with ethyl acetate, washed and dried, the solvent was evaporated and the product was obtained after crystallization (melting point: 170.9 ° C).

(d6-DMSO? 500 MHz5 RT): 8.83 (d? J = 5.3 51 Η); 8.31 (d? J = 7.0，1H); 8.12-8.08 (m，2H); 8.01 (d，J = 5.35 1H); 7.79 (d，J = 8.4，2H); 7.64-7.62 (m，1H); 7.57 (t，J = 7.9，1H); 7 · 4 6 (d，J = 8 · 2，2 H); 4 · 2 4 (quintett，J = 7 · 2，1H); 3.58 (s， 3H); 3.04-2.98 (m5 2H); 2.60-2.51 (m? 2H); 1.24 (d5 J = 7.3? 3H)(d6-DMSO? 500 MHz5 RT): 8.83 (d? J = 5.3 51 Η); 8.31 (d? J = 7.0, 1H); 8.12-8.08 (m, 2H); 8.01 (d, J = 5.35 1H) ; 7.79 (d, J = 8.4, 2H); 7.64-7.62 (m, 1H); 7.57 (t, J = 7.9, 1H); 7 · 4 6 (d, J = 8 · 2, 2 H); 4 · 2 4 (quintett, J = 7 · 2, 1H); 3.58 (s, 3H); 3.04-2.98 (m5 2H); 2.60-2.51 (m? 2H); 1.24 (d5 J = 7.3? 3H)

類似實例54中說明，但利用適當起始材料（式I之化合物 ，其中R4為如下表7中所定義）得到如表7中所定義之 iH-NMR^dpDMSO，500 MHz，RT)或熔點： -40- 200302728 (36) 表7 "實例Similar to that illustrated in Example 54 but using appropriate starting materials (compounds of formula I, where R4 is as defined in Table 7 below) to obtain iH-NMR ^ dpDMSO, 500 MHz, RT) or melting point as defined in Table 7: -40- 200302728 (36) Table 7 " Examples

R4EXR4EX

熔點/H-NMR 55Melting point / H-NMR 55

12.61 (br.); 8.82 (d, J = 5.3,1H)； 8.09 -8.06 (m, 3H); 8.01 (d, J = 5.2,1H); 7.78 (d, J = 8.7, 2H); 7.63 - 7.61 (m, 1H); 7.58 -7.54 (m, 1H); 7.45 (d, J = 8.3, 2H); 7.21-7.13 (m, 5H); 4.40 - 4.35 (m, 1H); 3.00 (dd, J = 13.9, 4.8,1H); 2.79 (dd, J = 13.8, 9.7, 1H); 2.69 (t,J^ 7.3, 2H)； 2.12 -2.08 (m, 2H); 1.79r(^iinteU J = 7·3, 2H)12.61 (br.); 8.82 (d, J = 5.3,1H); 8.09 -8.06 (m, 3H); 8.01 (d, J = 5.2,1H); 7.78 (d, J = 8.7, 2H); 7.63- 7.61 (m, 1H); 7.58 -7.54 (m, 1H); 7.45 (d, J = 8.3, 2H); 7.21-7.13 (m, 5H); 4.40-4.35 (m, 1H); 3.00 (dd, J = 13.9, 4.8, 1H); 2.79 (dd, J = 13.8, 9.7, 1H); 2.69 (t, J ^ 7.3, 2H); 2.12 -2.08 (m, 2H); 1.79r (^ iinteU J = 7 · 3, 2H)

8.82 (d, J = 5.5, 1H); 8.13 - 8.12 (m, 1H); 8.11 - 8.09 (m, 1H); 8.00 (d, J = 5.2, 1 H); 7.79 (d, J = 8.2, 2H); 7.65 - 7.62 (m, 1H); 7.57 (t, J = 7.9, 1H); 7.46 (d, J = 8.2, 2H); 3.35 - 3.21 (m, 4H); 2.99 - 2.96 (m, 2H); 2.70 - 2.67 (m, 2H); 1.09 (t, J = 7.0, 3H); 0.98 (t, J = 7.0t 3H)_ 578.82 (d, J = 5.5, 1H); 8.13-8.12 (m, 1H); 8.11-8.09 (m, 1H); 8.00 (d, J = 5.2, 1 H); 7.79 (d, J = 8.2, 2H ); 7.65-7.62 (m, 1H); 7.57 (t, J = 7.9, 1H); 7.46 (d, J = 8.2, 2H); 3.35-3.21 (m, 4H); 2.99-2.96 (m, 2H) ; 2.70-2.67 (m, 2H); 1.09 (t, J = 7.0, 3H); 0.98 (t, J = 7.0t 3H) _ 57

8.82 (d, J = 5.3,1H); 8.12 - 8.07 (m, 2H)； 8,00 (d, J = 5.3, 1H); 7.83 (t, J = 5.6,1H); 7.78 (d, J = 8.8, 2H); 7-63 (m, 1H); 7.56 (t, J = 7.8, 1H); 7.45 (d, J = 8.6, 2H); 3.04 :?·96 (m,—盤 2H); 2.07 (s, 6H); 1.47 (^iintett/J = 7.1, 2H) __ 588.82 (d, J = 5.3,1H); 8.12-8.07 (m, 2H); 8,00 (d, J = 5.3, 1H); 7.83 (t, J = 5.6,1H); 7.78 (d, J = 8.8, 2H); 7-63 (m, 1H); 7.56 (t, J = 7.8, 1H); 7.45 (d, J = 8.6, 2H); 3.04:? · 96 (m,-plate 2H); 2.07 (s, 6H); 1.47 (^ iintett / J = 7.1, 2H) __ 58

(400 MHz): 8.82 (d, J = 5.3,1H); 8.31 (d, j = 7.7, 1H)； 8.11 - 8.08 (m, 2H)； 8.01 (d, J = 5.3,1H)； 7.77 (d, J = 8.7, 2H); 7.64 -7.61 (m, 1H); 7.56 (t, J = 7.7,1H); 7.44 (d, J = 8.2, 2H); 4.28 - 4.23 (m, 1H)； 3.58 (s, 3H); 2.97 (m, 2H); 2.62 - 2.48 (m); 2.25 (t, J = 7.5, 2H); 1.90 (m, 1H); 1.75 (m, 1H) ·' 59(400 MHz): 8.82 (d, J = 5.3, 1H); 8.31 (d, j = 7.7, 1H); 8.11-8.08 (m, 2H); 8.01 (d, J = 5.3, 1H); 7.77 (d , J = 8.7, 2H); 7.64 -7.61 (m, 1H); 7.56 (t, J = 7.7,1H); 7.44 (d, J = 8.2, 2H); 4.28-4.23 (m, 1H); 3.58 ( s, 3H); 2.97 (m, 2H); 2.62-2.48 (m); 2.25 (t, J = 7.5, 2H); 1.90 (m, 1H); 1.75 (m, 1H) '59

12.64 (br); 8.82 (d, J = 5.2,1H); 8.21 (d, J = 8.0,1H); 8.11 - 8.07 (m, 2H); 8.01 (df J = 5.3, 1H)； 7.77 (d, J = 8.5, 2H)； 7.64 -7.61 (m, 1H); 7.56 (t, J = 7.9,1H); 7.45 (d, J = 8.3, 2H); 7.22 - 7.11 (m, 5 H); 4.40 (cjt, 1H); 3.01 (dd, J = 13.8, 5.1,1H); 2.92 - 2.88 (m, 2H); 2.83 (dd, J = 13.7, 9.1, 1H); 2.55-2.43 (m)_ o12.64 (br); 8.82 (d, J = 5.2,1H); 8.21 (d, J = 8.0,1H); 8.11-8.07 (m, 2H); 8.01 (df J = 5.3, 1H); 7.77 (d, J = 8.5, 2H); 7.64 -7.61 (m, 1H); 7.56 (t, J = 7.9,1H); 7.45 (d, J = 8.3, 2H); 7.22-7.11 (m, 5 H); 4.40 ( cjt, 1H); 3.01 (dd, J = 13.8, 5.1, 1H); 2.92-2.88 (m, 2H); 2.83 (dd, J = 13.7, 9.1, 1H); 2.55-2.43 (m) _ o

8.83 (d, J = 5.3, 1H); 8.30 (d, J = 7.5, 1H); 8.12 - 8.08 (m, 2H); 8.01 (d, J = 5.3, 1H); 7.78 (d, J = 8.9, 2H); 7.64 - 7.62(m, 1H); 7.57 (t, J = 7.9, 1H); 7.45 (d, J = 8.4, 2H); 4.27 (dt, J = 5.3, 8.3, 1H); 3.59 (s, 3H); 3.55 (s, 3H); 3.04 - 2.9Θ (m, 2H); 2.62 - 2.49 (m, 2H); 2.38 - 2.31 (m, 2H)； 1.99 -1.92 (m, 1H); 1.83 -1J6 (m, 4H) -41 - 200302728 (37) 68.83 (d, J = 5.3, 1H); 8.30 (d, J = 7.5, 1H); 8.12-8.08 (m, 2H); 8.01 (d, J = 5.3, 1H); 7.78 (d, J = 8.9, 2H); 7.64-7.62 (m, 1H); 7.57 (t, J = 7.9, 1H); 7.45 (d, J = 8.4, 2H); 4.27 (dt, J = 5.3, 8.3, 1H); 3.59 (s , 3H); 3.55 (s, 3H); 3.04-2.9Θ (m, 2H); 2.62-2.49 (m, 2H); 2.38-2.31 (m, 2H); 1.99 -1.92 (m, 1H); 1.83- 1J6 (m, 4H) -41-200302728 (37) 6

o- 8.83 (d, J = 5.2, 1H); 8.19 (d, J = 7.5, 1H); 8.11 « 8.07 (m, 2H); 8.02 (d, J = 5.3, 1H); 7J8 (d, J = 8.6, 2H); 7.64 - 7.62(m, 1H); 7.57 (t, J = 7.8, 1H); 7.47 (d, J = 8.1, 2H); 4.22 - 4.18 (m, 1H); 3.55 (two singlets, 6H); 2.78 (t, J = 7.4, 2H); 2.30 (t, J = 7.8, 2H); 2.18 (t, J = 7.2, 2H); 1.96 -1.84 (m, 3H); 1.80-1.72 (m, 1H)o- 8.83 (d, J = 5.2, 1H); 8.19 (d, J = 7.5, 1H); 8.11 «8.07 (m, 2H); 8.02 (d, J = 5.3, 1H); 7J8 (d, J = 8.6, 2H); 7.64-7.62 (m, 1H); 7.57 (t, J = 7.8, 1H); 7.47 (d, J = 8.1, 2H); 4.22-4.18 (m, 1H); 3.55 (two singlets, 6H); 2.78 (t, J = 7.4, 2H); 2.30 (t, J = 7.8, 2H); 2.18 (t, J = 7.2, 2H); 1.96 -1.84 (m, 3H); 1.80-1.72 (m , 1H)

65 8.83 (d, J - 5.2, 1H); 8.10 -8.07 (m, 2H); 8.05 (d, J = 7.6, 1H); 8.01 (d, J = 5.2, 1H); 7.78 (d, J = 8.9, 2H); 7.63 - 7.61 (m, 1H); 7.57 (t, J = 7.9, 1H); 7.47 (d, J = 8.5, 2H)； 4.15 (dt, J = 5.0, 8.4, 1H)； 3.54 (s, 3H); 2.78 (m； 2H); 2.30 - 2.27 (m, 2H); 2.18 (t，J = 7:3, 2H); 1·96 -1.90 (m, 1H); 1.88 -1.82 (m, 2H); 1.78 -1.70 (m，1H) 8.83 (d, J = 5.5, 1H); 8.20 (d, J = 7.0, 1H); 8.11 - 8.08 (m, 2H); 8.02 (d, J = 5.2, 1H); 7J8 (d, J = 8.2,. 2H); 7.65 - 7.62 (m, 1H); 7.57 (t, J = 7*9, 1H); 7.47 (d, J = 7.9, 2H); 4.21 - 4.15 (m，1H); 3.54 (s, 3H); Σ?δ (ΐΤΤ="Τ：57έΗΡ:16 (tTJ == 7A 2H); 1.89 -1.82 (m, 2H); 1.18 (d, J = 7.3, 3H) 8.78 (d, J = 5.3,1H)； 8.15 (d, J = 7.3, 1H); 8.09 - 8.07 (m, 2H); 7.97 (d, J = 5,3, 1H); 7.84 (d, J =： 8.3, 2H); 7.65 - 7.62 (m, 1H); 7.58 - 7.55 (m, 1H); 7.52 (d, J = 8.3, 2Η);,4·90 (s, 2H); 4.35 - 4.28 (m, 1H); 4.02 (s, 2H); 3.58 (s, 3H); 1.25 (d, J = 7.3, 3H)65 8.83 (d, J-5.2, 1H); 8.10 -8.07 (m, 2H); 8.05 (d, J = 7.6, 1H); 8.01 (d, J = 5.2, 1H); 7.78 (d, J = 8.9 , 2H); 7.63-7.61 (m, 1H); 7.57 (t, J = 7.9, 1H); 7.47 (d, J = 8.5, 2H); 4.15 (dt, J = 5.0, 8.4, 1H); 3.54 ( s, 3H); 2.78 (m; 2H); 2.30-2.27 (m, 2H); 2.18 (t, J = 7: 3, 2H); 1.96 -1.90 (m, 1H); 1.88 -1.82 (m , 2H); 1.78 -1.70 (m, 1H) 8.83 (d, J = 5.5, 1H); 8.20 (d, J = 7.0, 1H); 8.11-8.08 (m, 2H); 8.02 (d, J = 5.2 , 1H); 7J8 (d, J = 8.2 ,. 2H); 7.65-7.62 (m, 1H); 7.57 (t, J = 7 * 9, 1H); 7.47 (d, J = 7.9, 2H); 4.21 -4.15 (m, 1H); 3.54 (s, 3H); Σ? Δ (ΐΤΤ = " T: 57ΗΗΡ: 16 (tTJ == 7A 2H); 1.89 -1.82 (m, 2H); 1.18 (d, J = 7.3, 3H) 8.78 (d, J = 5.3, 1H); 8.15 (d, J = 7.3, 1H); 8.09-8.07 (m, 2H); 7.97 (d, J = 5, 3, 1H); 7.84 (d, J =: 8.3, 2H); 7.65-7.62 (m, 1H); 7.58-7.55 (m, 1H); 7.52 (d, J = 8.3, 2Η) ;, 4.90 (s, 2H); 4.35-4.28 (m, 1H); 4.02 (s, 2H); 3.58 (s, 3H); 1.25 (d, J = 7.3, 3H)

8.82 (d, 1H); 8.12 - 8.07 (m, 2H); 8.02 (d, J = 7.8, 1H); 8.00 (d, J = 5.3, 1H)； 7.84 7.7? (d, J = 8.4, 2H); 7.63 - 7.61 (m, 1H); 7.55 (t, 1H); 7.45 (d, J = 8.2, 2H); 4.12-4.07 (m, 1H); 3.01-2.97 (m, 4H); 2.48-2.45 (m,2H); 1.80 (s, 3H) 66 r O 8.82 (d, 1H); 8.12 - 8.07 (m, 2H); 8.00 (d, J = 5.3, 1H); 7.78 (d, J = 8.3, 2H); 7.63 (m, 1H); 7,56 (t, J = 7.9,1H); 7.45 (d, J = 8.i, 2H); 3.25 - 3.16 (mf 4H); 2.80 (t, J = 7.3, 2H); 2.31 (t, J = 7.3, 2H); 1.85 (quintett, J = 7.3, 2H); 1.00 (t, J=7.1, 3H); 0.92 (t, J=7.1,3H) 67 H I 〇 8.83 (df J = 5.3,1H); 8,11 - 8.07 (m, 2H); 8.01 (d, J = 5.3, 1H); 7.80 - 7.73 (m, 3H); 7.62 (d, 1H); 7.55 (t, 1H); 7.45 (d, J = 8.3, 2H); 2.95 (m, 2H); 2.7^ (t, J = 7.2, 2H); 2.05(s) -42- 2003027288.82 (d, 1H); 8.12-8.07 (m, 2H); 8.02 (d, J = 7.8, 1H); 8.00 (d, J = 5.3, 1H); 7.84 7.7? (D, J = 8.4, 2H) ; 7.63-7.61 (m, 1H); 7.55 (t, 1H); 7.45 (d, J = 8.2, 2H); 4.12-4.07 (m, 1H); 3.01-2.97 (m, 4H); 2.48-2.45 ( m, 2H); 1.80 (s, 3H) 66 r O 8.82 (d, 1H); 8.12-8.07 (m, 2H); 8.00 (d, J = 5.3, 1H); 7.78 (d, J = 8.3, 2H ); 7.63 (m, 1H); 7,56 (t, J = 7.9,1H); 7.45 (d, J = 8.i, 2H); 3.25-3.16 (mf 4H); 2.80 (t, J = 7.3 , 2H); 2.31 (t, J = 7.3, 2H); 1.85 (quintett, J = 7.3, 2H); 1.00 (t, J = 7.1, 3H); 0.92 (t, J = 7.1, 3H) 67 HI 〇 8.83 (df J = 5.3,1H); 8,11-8.07 (m, 2H); 8.01 (d, J = 5.3, 1H); 7.80-7.73 (m, 3H); 7.62 (d, 1H); 7.55 ( t, 1H); 7.45 (d, J = 8.3, 2H); 2.95 (m, 2H); 2.7 ^ (t, J = 7.2, 2H); 2.05 (s) -42- 200302728

(38)(38)

ο R4EX 為 、 將6.5克3-[5-(2 -氯棱基-乙乳基）-戊基氧ι化]-丙酸氯於 10毫升CH2C12中之溶液逐滴加入1克Ν-[4-(3 -氯-苯基）·嘧 啶-2-基]-Ν-(4·三氟甲基-苯基）-胺、10毫克二甲基胺吡啶 及2.7毫升二異丙基乙基胺於CH2C12中之混合物中。將得 到的混合物於室溫攪拌，冷卻並將丙腈及水加入；再將混 合物攪拌。將得到的混合物以乙酸乙酯萃取。將形成的有 機相清洗、乾燥，，將溶劑蒸發並得到產物。 1H-NMR(d6-DMSO, 500 MHz，RT): 8.83 (d，J = 5.2，lH); 8.12 (t，J=1.9，1H); 8.10 (dt，J = 7.6，1.5，1H); 8.02 (d，J = 5.4, 1H); 7.79 (d，J = 8.3，2H); 7.64 (m，1H); 7.57 (t，J = 7.9, 1H); 7.44 (d，J=8.1，2H); 3.68 (t，J = 6.4，2H); 3.51 (t， J = 6.4, 2H); 3.03 (t，J = 6.5, 2H); 2·39 (t5 J = 6.3，2H); 1.47-1.39 (m，4H); 1.28-1.21 (m，2H) -43-ο R4EX is a solution of 6.5 g of 3- [5- (2-chloropyridyl-ethyllactyl) -pentyloxy] -propionic acid chloride in 10 ml of CH2C12 was added dropwise to 1 g of N- [4 -(3-chloro-phenyl) · pyrimidin-2-yl] -N- (4 · trifluoromethyl-phenyl) -amine, 10 mg of dimethylamine pyridine and 2.7 ml of diisopropylethylamine In a mixture in CH2C12. The resulting mixture was stirred at room temperature, cooled and propionitrile and water were added; the mixture was stirred. The resulting mixture was extracted with ethyl acetate. The formed organic phase was washed, dried, the solvent was evaporated and the product was obtained. 1H-NMR (d6-DMSO, 500 MHz, RT): 8.83 (d, J = 5.2, 1H); 8.12 (t, J = 1.9, 1H); 8.10 (dt, J = 7.6, 1.5, 1H); 8.02 (d, J = 5.4, 1H); 7.79 (d, J = 8.3, 2H); 7.64 (m, 1H); 7.57 (t, J = 7.9, 1H); 7.44 (d, J = 8.1, 2H); 3.68 (t, J = 6.4, 2H); 3.51 (t, J = 6.4, 2H); 3.03 (t, J = 6.5, 2H); 2.39 (t5 J = 6.3, 2H); 1.47-1.39 (m , 4H); 1.28-1.21 (m, 2H) -43-

Claims (1)

200302728 拾、申請專利範圍 1. 一種下式之化合物200302728 Patent application scope 1. A compound of the following formula 其中 Ri為鹵素或鹵化（(^_4)烷基， R2為氫、鹵素或鹵化（Ci-4)燒基， R3為鹵素或鹵化d-4)烷基， R4為氫、（Cu)烷基、羥（Cm)烷基或下列式之族群 -CO-R5 、 -CO-(CH2)m-OR6、 -CO-CO'R7、 -CO-CO-ORg、 -CO-N(R9Ri〇)、 -CO-(CH2)n-CO-Rn、 -co-(chr15)-o-(ch2)0-co-r"、 -C0-(CH2)p_0-(CH2)q-0-(CH2)r_R16、 -C0-0-(CH2)s-0-C0-R17、 -C0-0-(CH2)t-N(R18R19)、 200302728 -co-o-(ch2)u-nh-co-ch(nh2)-r2〇、或 -co-o-(ch2)w-nh-co-r17，其中 R5為氫、（Cu)烷基、（C3.8)環烷基、胺基、（Ci.4) 4 烷胺基、二（Ci-4)烷胺基、芳基或為具有1至4 ^ 個選自N、Ο或S之雜原子的5或6員雜環系統 之雜環基， R6為氫、（Cm)烷基、（C3_8)環烷基、芳基、經 具有1至4個選自Ν、Ο或S之雜原子的5或6員 P 雜環系統之雜環基取代的烷基、胺基 烷基胺（C^)烷基、羥（C^)烷基、羥（Cy)烷 基胺（Cu)烷基或胺基酸殘基，如 -CH2-CH(NH2)-COOH，Where Ri is halogen or halogenated ((4_4) alkyl, R2 is hydrogen, halogen or halogenated (Ci-4) alkyl, R3 is halogen or halogenated (d-4) alkyl, R4 is hydrogen, (Cu) alkyl , Hydroxy (Cm) alkyl or a group of the formula -CO-R5, -CO- (CH2) m-OR6, -CO-CO'R7, -CO-CO-ORg, -CO-N (R9Ri〇), -CO- (CH2) n-CO-Rn, -co- (chr15) -o- (ch2) 0-co-r ", -C0- (CH2) p_0- (CH2) q-0- (CH2) r_R16 , -C0-0- (CH2) s-0-C0-R17, -C0-0- (CH2) tN (R18R19), 200302728 -co-o- (ch2) u-nh-co-ch (nh2)- r20, or -co-o- (ch2) w-nh-co-r17, where R5 is hydrogen, (Cu) alkyl, (C3.8) cycloalkyl, amine, (Ci.4) 4 alkane Amine group, di (Ci-4) alkylamino group, aryl group or heterocyclic group of 5 or 6 membered heterocyclic system having 1 to 4 ^ heteroatoms selected from N, 0 or S, R6 is hydrogen, (Cm) alkyl, (C3-8) cycloalkyl, aryl, alkyl substituted with a heterocyclic group of a 5 or 6-membered P heterocyclic system having 1 to 4 heteroatoms selected from N, 0 or S, Aminoalkylamine (C ^) alkyl, hydroxy (C ^) alkyl, hydroxy (Cy) alkylamine (Cu) alkyl or amino acid residues, such as -CH2-CH (NH2) -COOH, R7及R8各自獨立為（Ci.4)烷基、（c3.8)環烷基、 芳基或為具有1至4個選自Ν、Ο或S之雜原子 的5或6員雜環系統之雜環基， 119及R1G各自獨立為氫或（Cm)烷基或R9及R10 其中之一為氫而另一為（C3-8)環烷基、（Cu) 烷基、芳基或雜環基， Rii 為（<^_4)烷基、-OR12、NR13R14、胺基酸、其 (Cm)烷基酯或其二（Cm)烷基酯， R12為氫或（<^_4)烷基， 及Rl4各自獨立為氫、（C!_4)烷基、胺（Cb6) 烷基、（Ci-4)烷基胺（Ch)烷基、二（C!·〗）烷基 -2- 200302728R7 and R8 are each independently (Ci.4) alkyl, (c3.8) cycloalkyl, aryl or a 5 or 6-membered heterocyclic system having 1 to 4 heteroatoms selected from N, 0 or S Heterocyclic group, 119 and R1G are each independently hydrogen or (Cm) alkyl or one of R9 and R10 is hydrogen and the other is (C3-8) cycloalkyl, (Cu) alkyl, aryl or hetero Ring group, Rii is (< ^ _ 4) alkyl, -OR12, NR13R14, amino acid, its (Cm) alkyl ester or its di (Cm) alkyl ester, R12 is hydrogen or (< ^ _ 4) Alkyl and R14 are each independently hydrogen, (C! _4) alkyl, amine (Cb6) alkyl, (Ci-4) alkylamine (Ch) alkyl, di (C! ·)) Alkyl-2 -200302728 胺（Ci.6)烷基， R15為氫或（Ci-4)烷基， Rl6為氫、（Ci.4)燒基、叛基或叛酸自旨， · Rl7為胺（Ci-4)坑基、（Ci_4)fe基胺（Ci.4)燒基或 * 二（C!-4)烷基胺（CL4)烷基， Rl8為氫或（Cm)烷基， R19為羥（CL4)烷基， R20為（Cm)烷基或羥（Cb4)烷基， m為0至4， η為2至8， 〇為0至4， ρ為0至4， q為1至8， r為0至4， s為1至4， t為1至4， u為1至6及 w為1至6。 2.根據申請專利範圍第1項之化合物，其中 -Ri為氯或三氟甲基， i -R2為氫或三氟甲基， . -R3為氯、氟或三氟甲基， -R4為氫、（Ci-4)烷基（如甲基）、羥（Ci-4)烷基（如羥甲基） 、或下列式之族群 200302728Amine (Ci.6) alkyl, R15 is hydrogen or (Ci-4) alkyl, Rl6 is hydrogen, (Ci.4) alkyl, sulphydryl or acid, and Rl7 is amine (Ci-4) Pit group, (Ci_4) fe-based amine (Ci.4) alkyl or * di (C! -4) alkylamine (CL4) alkyl, R18 is hydrogen or (Cm) alkyl, R19 is hydroxyl (CL4) Alkyl, R20 is (Cm) alkyl or hydroxy (Cb4) alkyl, m is 0 to 4, η is 2 to 8, 0 is 0 to 4, ρ is 0 to 4, q is 1 to 8, and r is 0 to 4, s is 1 to 4, t is 1 to 4, u is 1 to 6, and w is 1 to 6. 2. The compound according to item 1 of the scope of patent application, wherein -Ri is chloro or trifluoromethyl, i -R2 is hydrogen or trifluoromethyl, -R3 is chloro, fluoro or trifluoromethyl, and -R4 is Hydrogen, (Ci-4) alkyl (e.g. methyl), hydroxy (Ci-4) alkyl (e.g. methylol), or a group of the formula 200302728 -C Ο - R 5、 -CO-(CH2)m-OR6、 -CO-CO-R7、 -CO-CO-OR8、 -CO-N(R9Ri0)、-C Ο-R 5, -CO- (CH2) m-OR6, -CO-CO-R7, -CO-CO-OR8, -CO-N (R9Ri0), -CO-(CH2)n-CO-Ru ^ .CO-(CHR15)-〇-(CH2)〇-CO-Rn ^ -C0-(CH2)p-0-(CH2)q-0-(CH2)r-R16 ^ -co-o-(ch2)s-o-co-r17、 -C0-0-(CH2)t-N(R18R19)、 -CO-O-(CH2)u-NH-CO-CH(NH2)-R20、或 -co-o-(ch2)w-nh-co-r17，其中 R5為氫、（Cm)烷基、（C3-8)環烷基、二甲胺基 、芳基或為具有1個O作為雜原子之6員雜環系 統之雜環基（如四氫吡喃基），-CO- (CH2) n-CO-Ru ^ .CO- (CHR15) -〇- (CH2) 〇-CO-Rn ^ -C0- (CH2) p-0- (CH2) q-0- (CH2) r-R16 ^ -co-o- (ch2) so-co-r17, -C0-0- (CH2) tN (R18R19), -CO-O- (CH2) u-NH-CO-CH (NH2)- R20, or -co-o- (ch2) w-nh-co-r17, where R5 is hydrogen, (Cm) alkyl, (C3-8) cycloalkyl, dimethylamino, aryl, or has 1 A heterocyclic group (such as tetrahydropyranyl) of a 6-membered heterocyclic system with O as a heteroatom, R6為氫、d-4)烷基、經具有1或2個選自Ν或Ο 之雜原子的5或6員雜環系統之雜環基取代的 (C i_2)烷基（如包括未經取代之吡咯啶、1，4-氧氮陸圜及哌畊、及受如（(^_2)烷基或（C!-2) 羥烷基取代之哌畊）、胺基（C!-4)烷基、（Cy) 烷基胺（C i _ 4 )烷基、二（C i . 2 )烷基胺（C i _ 4 )烷基 、羥（Cm)烷基、羥（Cm)烷基胺（<^_2)烷基或 胺基酸殘基，如-CH2-CH(NH2)-COOH， 117及r8各自獨立為烷基或苯基， -4- 200302728R6 is hydrogen, d-4) alkyl, (C i_2) alkyl substituted with a heterocyclyl of a 5- or 6-membered heterocyclic system having 1 or 2 heteroatoms selected from N or 0 (including Substituted pyrrolidine, 1,4-oxazepine and piperin, and piperin substituted by ((^ _2) alkyl or (C! -2) hydroxyalkyl), amine (C! -4 ) Alkyl, (Cy) alkylamine (C i _ 4) alkyl, di (C i. 2) alkylamine (C i _ 4) alkyl, hydroxy (Cm) alkyl, hydroxy (Cm) alkane ≪ ^ _ 2) alkyl or amino acid residues, such as -CH2-CH (NH2) -COOH, 117 and r8 are each independently an alkyl or phenyl group, -4- 200302728 R9&R1G各自獨立為氫或（C^-2)烷基， Rll 為（Ci_2)fe 基、-OR12、NR13R14、胺基酸、其 (Ci-2)烷基酯或其二（CL2)烷基酯，較佳為由 丙胺酸、苯基丙胺酸、穀胺酸及賴胺酸組成 之族群選出之胺基酸，其中結合係經由α -胺基或於如賴胺酸的情況中經由ε -胺基達 成， Rl2為氮或（Ci_2)坑基5 Ri3及Rl4各自獨立為氫、（Ci-2)烷基、胺（C〗-4) 烷基、（Ci-2)烷基胺（Ci-4)烷基、二（Ci_2)烷基 胺（c 1 _ 4 )燒基’ R15為氫或（Cm)烷基， Ri 6為氫、（Ci-2)烷基、羧基或羧酸酯， R 1 7為胺（C 1 - 2 )燒基’ R18為氫或（Ci.2)烷基， Rl9為羥（Ci-2)烷基， R2〇為（Ch)烷基或羥（Cm)烷基， m為0或1， η為2至4， 〇為0或1， ρ為0至2， q為2至5， r為0至2， s為2， 200302728 t為2， u為1至3及 w為1至3。 3. 根據申請專利範圍第1或第2項式I之化合物，其中 -Ri為氯， -R2為氫’ -R3為二氣甲基及 -R4為氫。 4. 根據申請專利範圍第1或第2項式I之化合物，其中 -Ri為氯， -R2為氫’ -R3為三氟甲基及 -r4為式-co-o-(ch2)2-n[(c2h5oh)(ch3)]之基團。 5 .根據申請專利範圍第1或第2項之化合物，其係為鹽之 形式。 6. 一種根據申請專利範圍第1或第2項之化合物於製備用 於治療I g E合成調節的疾病、自體免疫疾病、胃腸疾病 及移植的慢性排斥之藥劑之用途。 7. 根據申請專利範圍第1或第2項之化合物，其係作為藥 劑。 8. 一種醫藥組合物，包含根據申請專利範圍第1或第2項 之化合物與至少一種醫藥賦形劑結合。 9. 一種胺類的用途，其經 -經苯基取代之嘧啶；及R9 & R1G are each independently hydrogen or (C ^ -2) alkyl, and Rll is (Ci_2) fe group, -OR12, NR13R14, amino acid, its (Ci-2) alkyl ester or its di (CL2) alkane Amino esters, preferably amino acids selected from the group consisting of alanine, phenylalanine, glutamic acid, and lysine, wherein the bond is via an α-amino group or, in the case of lysine, via ε -The amine group is reached, Rl2 is nitrogen or (Ci_2) pit group 5 Ri3 and Rl4 are each independently hydrogen, (Ci-2) alkyl, amine (C) -4) alkyl, (Ci-2) alkylamine ( Ci-4) alkyl, di (Ci_2) alkylamine (c 1 _ 4) alkyl, R15 is hydrogen or (Cm) alkyl, Ri 6 is hydrogen, (Ci-2) alkyl, carboxyl or carboxylic acid Ester, R 1 7 is amine (C 1-2) alkyl; R 18 is hydrogen or (Ci.2) alkyl, R 19 is hydroxy (Ci-2) alkyl, and R 2 is (Ch) alkyl or hydroxy ( Cm) alkyl, m is 0 or 1, η is 2 to 4, 〇 is 0 or 1, ρ is 0 to 2, q is 2 to 5, r is 0 to 2, s is 2, 200302728 t is 2, u is 1 to 3 and w is 1 to 3. 3. The compound of formula I according to item 1 or 2 of the scope of the patent application, wherein -Ri is chlorine, -R2 is hydrogen ', -R3 is a dimethyl group, and -R4 is hydrogen. 4. The compound of formula I according to item 1 or 2 of the scope of the patent application, wherein -Ri is chlorine, -R2 is hydrogen ', -R3 is trifluoromethyl and -r4 is formula -co-o- (ch2) 2- n [(c2h5oh) (ch3)]. 5. The compound according to item 1 or 2 of the scope of patent application, which is in the form of a salt. 6. Use of a compound according to item 1 or 2 of the scope of patent application for the preparation of a medicament for the treatment of Ig E synthesis-modulated diseases, autoimmune diseases, gastrointestinal diseases, and chronic rejection of transplantation. 7. The compound according to item 1 or 2 of the scope of patent application, which is used as a medicine. 8. A pharmaceutical composition comprising a compound according to item 1 or 2 of the scope of patent application in combination with at least one pharmaceutical excipient. 9. Use of an amine, which is -pyrimidine substituted with phenyl; and 200302728 "苯基，及 -第三種取代基，如於申請專利範圍第1至5項中定義之 R4， 取代，其係用於製備治療Ϊ g E合成調節的疾病、自體免 疫疾病、胃腸疾病及移植的慢性排斥之藥劑。 200302728 陸、（一）、本案指定代表爵為：第 圖 (二）、本代表圖之元件代表符號簡單說明：200302728 " Phenyl, and-a third substituent, such as R4 as defined in items 1 to 5 of the scope of patent application, is substituted for the treatment of diseases regulated by 调节 g E synthesis, autoimmune diseases, Chronic rejection for gastrointestinal diseases and transplants. 200302728 Lu, (1), the designated representative of this case is: Figure (2), the component representative symbols of this representative map are simply explained: 柒、本案若有化學式時，請揭示最能顯示發明特徵的化學式：柒 If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention:
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